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Autonomic nerve dysfunction and impaired diabetic wound healing: The role of neuropeptides
Autonomic Neuroscience: Basic and Clinical 223 (2020) 102610
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Review
Autonomic nerve dysfunction and impaired diabetic wound healing: The role of neuropeptides Georgios Theocharidis, Aristidis Veves
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Joslin-Beth Israel Deaconess Foot Center and The Rongxiang Xu, MD, Center for Regenerative Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
A B S T R A C T
Lower extremity ulcerations represent a major complication in diabetes mellitus and involve multiple physiological factors that lead to impairment of wound healing. Neuropeptides are neuromodulators implicated in various processes including diabetic wound healing. Diabetes causes autonomic and small sensory nerve fibers neuropathy as well as inflammatory dysregulation, which manifest with decreased neuropeptide expression and a disproportion in pro- and anti- inflammatory cytokine response. Therefore to fully understand the contribution of autonomic nerve dysfunction in diabetic wound healing it is crucial to explore the implication of neuropeptides. Here, we will discuss recent studies elucidating the role of specific neuropeptides in wound healing.
1. Introduction The skin is densely innervated by an interconnected system of highly specialized afferent sensory and efferent autonomic nerve fibers (Roosterman et al., 2006; Ansel et al., 1997). Cutaneous autonomic nerve fibers almost completely derive from sympathetic neurons and albeit very effective, they represent only a minority of skin nerve fibers in comparison with sensory nerves. In addition, as opposed to sensory nerves, the distribution of autonomic nerve fibers is restricted to the dermis, innervating blood vessels, lymphatic vessels, erector pili muscles, apocrine and eccrine glands, and hair follicles. Therefore, cutaneous autonomic nerve fibers take part in the modulation of blood circulation, lymphatic function, and skin appendages regulation (Vetrugno et al., 2003). Diabetic patients' skin exhibits motor, sensory and autonomic fiber denervation: sensory neuropathy restricts the sensations of pain, temperature, pressure and others; autonomic denervation leads to arteriovenous shunting, thereby causing vasodilation in small arteries; motor neuropathy induces weakness and wasting of small intrinsic muscles (DeFronzo et al., 2015). Importantly, microcirculation is affected in the diabetic neuropathic foot, mainly through impairment of both endothelium dependent and independent vasodilation (Arora et al., 2002) and peripheral blood flow is elevated and associated with arteriovenous shunting (Edmonds et al., 1982; Boulton et al., 1982). Finally, another consequence of autonomic denervation is sudomotor dysfunction that leads to dry skin and callus formation that play an important role in the development of diabetic foot ulceration. A growing body of studies in both patients and animal models points to a synergistic role of cutaneous nerve fibers and the immune system in
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mediating wound healing. The regulation of the healing response is realized through intricate interplay of components of the local immune and nervous system, which is further regulated via endocrine feedback (Pradhan et al., 2011; Pradhan et al., 2009; Quattrini et al., 2004). Neuropeptides are neuronal short-chain polypeptides that act as signaling molecules affecting numerous processes. Cutaneous nerve fibers and inflammatory cells such as monocytes, macrophages and eosinophils are known to release neuromodulators including cytokines and neuropeptides that regulate the activity of specific cytokine and neuropeptide receptors on a variety of skin cells including mature T and B cells, Langerhans cells, endothelial cells, mast cells, fibroblasts and keratinocytes resulting to the direct activation of G-protein signaling cascades (Roosterman et al., 2006; Luger, 2002). Fig. 1 summarizes how diabetes and neuropeptide expression dysregulation culminate in aberrant wound healing. Neuropeptide Y (NPY), Substance P (SP) and calcitonin gene related peptide (CRGP) are neuropeptides involved in modulating the immune response and wound healing. Further, other neuropeptides such as Melanocyte Stimulating Hormone (MSH) and Neurotensin are also neuromodulators and could potentially participate in impaired diabetic wound healing. These neuropeptides are released from autonomic nerve fibers as well as from cells within the dermis and the epidermis (Pradhan et al., 2011). Furthermore, these neuropeptides regulate the expression and function of numerous cytokines that are implicated and dysregulated in diabetes including IL-1, IL-6, IL-8, IL-10 and TNF-α (Pradhan et al., 2009).
Corresponding author at: Beth Israel Deaconess Medical Center, Palmer 321A, 1 Deaconess Rd, Boston, MA 02215, USA. E-mail address: [email protected] (A. Veves).
https://doi.org/10.1016/j.autneu.2019.102610 Received 15 March 2019; Received in revised form 22 November 2019; Accepted 25 November 2019 1566-0702/ © 2019 Elsevier B.V. All rights reserved.
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Fig. 1. Diabetic neuropathy and neuropeptide dysregulation contribute to lower extremity wound pathogenesis. Diabetes mellitus causes autonomic and small sensory nerve fibers neuropathy in the lower extremity as well as inflammatory dysregulation, which manifest with reduced neuropeptide expression and disproportion in pro- and anti- inflammatory cytokine response. Neuropeptides have a direct effect on leukocytes and further contribute to the cytokine imbalance. Also, cytokines and neuropeptides directly influence various skin cells including fibroblasts, keratinocytes and endothelial cells decreasing their proliferation and resulting in irregular angiogenesis, ECM production and reepithelialization. Reduced neovascularization, reepithelialization and dysregulation in remodeling and granulation tissue deposition, also affected by the abnormal cytokine expression profile, lead to impaired cutaneous wound healing. Adapted from Pradhan et al. (2009)
2. Neuropeptide Y (NPY)
3. Substance P (SP)
NPY is a highly conserved 36 amino acid polypeptide involved in dysregulated healing, and is one of the most abundant neurotransmitters in the mammalian central (CNS) and peripheral nervous system (PNS) (Pradhan et al., 2009). Besides the nerves, other nonneuronal cells have been reported to produce NPY, including megakaryocytes, liver, spleen, and ECs (Ericsson et al., 1987; Strand, 1999). NPY is mostly studied for its impact on the central nervous system, where it induces conservation of energy and counteracts the effects of Leptin. Thus, most of the NPY diabetes studies focus on its CNS effects (Pradhan et al., 2009). In the hypothalamus of both type 1 and type 2 diabetic patients, NPY expression is elevated while in the skin, it is decreased (Ahlborg and Lundberg, 1996; Wallengren et al., 1995; Levy et al., 1989). In a recent study NPY in the plasma of type 2 diabetic patients was found to be increased; however there is no data on dermal NPY expression for these patients. Baseline expression of NPY remains unchanged in a diabetic rabbit model of cutaneous wound healing (Pradhan et al., 2009). In addition, NPY has a pro-angiogenic effect and regulates elements of the innate and adaptive immune system (Pradhan et al., 2009). Specifically, NPY modulates cell migration, cytokine release from macrophages and helper T cells, antigen presentation as well as activation of natural killer cells and antibody production (Wheway et al., 2007; Groneberg et al., 2004; Bedoui et al., 2003). Platelet lysate derived NPY was recently shown to affect migration and angiogenesis potential of human adipose derived stromal cells and co-localized with endothelial markers CD31 and VEGF in difficult to heal wound samples treated with lysate (Businaro et al., 2018). NPY is mostly known to be associated with tendon and cartilage healing, but through its pro-angiogenic receptors NPY-2R and NPY-5R it also influences cutaneous healing (Zukowska et al., 2003a; Salo et al., 2008; Salo et al., 2007; Ackermann et al., 2002). Notably, in genetically modified mice where NPY-2R was deleted, a significant delay in cutaneous wound healing with decreased neovascularization was reported (Ekstrand et al., 2003). The enzyme dipeptidyl peptidase IV (DPP IV) that cleaves NPY into its pro-angiogenic form, which subsequently binds to NPY-2R and NPY-5R receptors, is enriched in aging mice (Zukowska et al., 2003b; Kitlinska et al., 2002). NPY is thus involved in both the inflammatory and angiogenic phases of wound healing. More research is necessary to elucidate the exact role of NPY in diabetic wound healing.
A member of the tachykinin neuropeptide family, SP is an 11 amino acid neuropeptide encoded by the TAC1 gene and is one of the main neuropeptides released by C-nociceptive fibers in response to injury (Olerud et al., 1999). In the last two decades, SP has emerged as a potent modulator of cutaneous wound healing among all healing associated neuropeptides. The pro-angiogenic function of SP has been demonstrated in both in vitro and in vivo experiments and importantly SP has been reported to have a critical role in wound site infiltration of polymorphonuclear leukocytes (Kohara et al., n.d.; Leal et al., 2015). SP also promotes proliferation in fibroblasts (Jung et al., 2016) and inhibits apoptosis through increasing the levels of BCL-2 and proliferating cell nuclear antigen in burn wounds (Jing et al., 2010). Noteworthy, SP has been found to be decreased in skin biopsies from both type 1 and type 2 diabetic patients (Lindberger et al., 1989) and SP mRNA and protein expression is diminished in a rabbit model of type 1 diabetes (Pradhan et al., 2009). Exogenous treatment of diabetic wounds with SP resulted in faster healing in both mice and rats (Leal et al., 2015; Park et al., 2016; Um et al., 2017; Zhu et al., 2016). In addition, topical administration of SP on excisional wounds in a db/db mouse model led to increased leukocyte infiltration compared to saline treatment at the early stages post-wounding, suggesting a role for SP involvement during early inflammation in wound healing (Scott et al., 2008). Moreover, the enzyme that inactivates SP, neutral endopeptidase (NEP) or neprilysin, is increased in diabetes and the use of a NEP inhibitor has been effective in accelerating diabetic wound healing (Spenny et al., 2002). In a rabbit model of diabetic wound-healing, our group has demonstrated reduced SP levels in the diabetic rabbit skin compared to non-diabetic and postwounding, both NPY and SP gene expression is diminished regardless of diabetic status (Pradhan et al., 2009). In endothelial cells, SP is an established vasodilating factor by inducing the production of nitric oxide, consequently enhancing endothelial permeability and leukocyte extravasation into the underlying tissues (Pernow, 1983). It has been recently reported to promote the mobilization of endothelial progenitor cells in the wounded tissue of a murine model of type 2 diabetes and increase the amount of Yes-associated protein expression in the dermis (Um et al., 2017). Furthermore, it acts as a potent chemoattractant for immune cells, promotes elevated expression of endothelial leukocyte adhesion molecule-1 on human microvascular endothelial cells and leukocyte function-associated antigen-1 (LFA-1) on murine endothelial cells and lymphocytes and can raise the levels of an array of 2
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gastrointestinal tissues as well as adrenal gland, hepatocytes and fibroblasts (Evers, 2006). The NT receptors neurotensin receptor 1, neurotensin receptor 2 and sortilin, are found throughout the CNS (Gross and Pothoulakis, 2007). According to different studies, NT may be involved in the pathogenesis of diabetes. Increased levels and total amounts of NT are found in the pancreas of obese (ob/ob) mice and in the intestine of both ob/ob and diabetic (db/db) mice (Sheppard et al., 1985). Similarly, insulin mediates NT concentrations in the pancreas, with high NT levels correlating with insulin deficiency in ob/ob and db/db mice (Berelowitz and Frohman, 1982). Nevertheless, in another study, NT expression was comparable between lean and diabetic mice. In addition, research in human patients did not reveal any difference in NT amounts between healthy nondiabetic subjects and lean and obese diabetic patients either pre- or postprandially (El-Salhy, 1998; Service et al., 1986). NT has been reported to affect wound healing by modulating cell functions of both innate and adaptive immunity, namely macrophages and T cells (Goldman et al., 1982; Koff and Dunegan, 1985; Lemaire, 1988; Garrido et al., 1992; Evers et al., 1994). NT expressing nerve fibers and NT mRNA are both present in the skin. Cutaneous NT activates skin mast cells causing secretion of histamine (Hartschuh et al., 1983; Donelan et al., 2006). In a recent study, in vitro treatment of keratinocytes and T cells with NT was shown to enhance migration and reduced the expression of TNF-α and IL-8. Interestingly, co-stimulation with SP led to decreased migratory capacity, while the angiogenesis in HUVEC cells was elevated (Mouritzen et al., 2018). NT also has an effect on cutaneous dendritic cells through downregulation of activation of inflammatory pathways JNK and NF-κB and reduction of expression of inflammatory cytokines IL-6, TNF-α and IL-10 (da Silva et al., 2011). Noteworthy, in two different mouse diabetic wound healing studies, delivery of NT with specially designed biomaterials enhanced wound closure. Collagen dressings functionalized with NT reduced inflammation and accelerated wound healing (Moura et al., 2014), whereas PLGA membranes loaded with NT also resulted in more rapid wound healing and decrease in inflammatory cytokine expression (Zheng et al., 2018). Therefore, topical delivery of NT could potentially be a promising treatment for diabetic foot ulcers.
inflammation linked cytokines including TGF-beta, TNF-α, IL-1β, IL-2, IL-8, IL-6 from dendritic and T cells, neutrophils, macrophages and fibroblasts (Matis et al., 1990; Vishwanath and Mukherjee, 1996; Delgado et al., 2003; Ho et al., 1997; Lai et al., 1998; Lai et al., 2002; Lambrecht, 2001; Lambrecht et al., 1999; Weinstock et al., 1988; O'Connor et al., 2004; Schratzberger et al., 1997; Bulut et al., 2008; Felderbauer et al., 2007). Hence by generating a pro-inflammatory environment within the wound site SP plays a crucial role in the inflammatory and angiogenic phases of wound healing. 4. Calcitonin gene related peptide (CGRP) CGRP is a 37 amino acid neuropeptide produced by an alternative splicing of the calcitonin gene (Wimalawansa, 1997). Just like NPY, CGRP is present in both the CNS and the PNS. In the PNS, CGRP is stored and released together with SP from capsaicin sensitive peripheral afferent neurons and is also a potent vasodilator (van Rossum et al., 1997; Holzer, 1988; Maggi, 1995). Notably, co-application of CGRP and SP to human skin induced long lasting vasodilation in a dose-dependent manner highlighting a synergistic effect of the two neuropeptides (Schlereth et al., 2016). Comparable to NPY, CGRP is found to be expressed outside the neurons in diverse organs such as the kidneys, liver, lungs and prostate (Russwurm et al., 2001). In peripheral tissues, CGRP receptors exist in the heart, liver, spleen, skeletal muscle, lungs, lymphocytes and the vasculature (van Rossum et al., 1997). A marked reduction of CGRP reactive fibers has been reported in the dermis of type 1 and type 2 diabetic patients (Lindberger et al., 1989). Diabetes has been shown to decrease the levels of CGRP in murine hearts, limit CGRP-mediated vasodilation in rats and diminish both CGRP and CGRP receptor expression in a rat model of diabetic cardiomyopathy (Chottova Dvorakova et al., 2005; Yorek et al., 2004; Oltman et al., 2008a; Oltman et al., 2009; Sheykhzade et al., 2000; Song et al., 2009; Dux et al., 2007; Adeghate et al., 2006). CGRP is also involved in the wound healing process by promoting neovascularization through elevated VEGF secretion from wound site cells and triggering the cAMP pathway (Toda et al., 2008; Haegerstrand et al., 1990). Moreover, CGRP induces release of both IL-1α and IL-8 in keratinocytes, IL-8 in the corneal epithelium, IL-1α, IL-8 and ICAM-1 in airway epithelium, IL-1β and TNF-α in macrophages, IL-1β, IL-6 and TNF-α in dental pulp fibroblasts, and acts as a chemoattractant for T cells, mediates lymphocyte proliferation and inhibits IL-2 expression (Zhang et al., 2006; Tran et al., 2000; Dallos et al., 2006; Yamaguchi et al., 2004; Yaraee et al., 2003; Wang et al., 1992; Foster et al., 1992). In animal models of diabetes CGRP was also decreased in tissues such as the heart and the dorsal root ganglion, but not much is known about its cutaneous expression (Oltman et al., 2008a; Oltman et al., 2009; Sheykhzade et al., 2000). In a recent study, vacuum-assisted treated wounds in a diabetic mouse model exhibited a significant increase in dermal and epidermal nerve fiber densities and in SP, CGRP, and nerve growth factor expression. In particular, the cyclical treatment mode correlated with the largest enhancement in granulation tissue production, and a slightly quicker wound closure rate (Younan et al., 2010). In CGRP-null mice (CGRP−/−), neovascularization and wound healing were impaired in comparison with control wild-type mice, and a reduction in the levels of VEGF from the wound granulation tissue was demonstrated (Toda et al., 2008). These findings indicate that the association of CGRP in wound healing is modulated through its impact on angiogenesis. Thus, exogenous CGRP addition may promote enhanced angiogenesis and wound healing.
6. Alpha-melanocyte-stimulating hormone (a-MSH) a-MSH is a 13 amino acid hormone and neuropeptide and belongs to the family of melanocortins, a number of structurally related peptides that not only participate in the regulation of pigmentation and cortisol expression but also modulate food intake, energy homeostasis, exocrine gland function, and inflammatory response (Gantz and Fong, 2003). aMSH is a proteolytic cleavage product of proopiomelanocortin (POMC) and is predominantly released from the pars intermedia region of the pituitary gland (Seidah et al., 1999). Noteworthy, significant amounts of a-MSH are present in the human skin (Thody et al., 1983; Slominski et al., 1993; Mazurkiewicz et al., 2000). A number of different cutaneous cell types including keratinocytes, fibroblasts, melanocytes and endothelial cells generate a-MSH and express melanocortin receptors (MCRs). Long-term activation of a-MSH decreases body weight and improves glucose metabolism in a model of diet-induced obesity (Lee et al., 2007). Two diabetic rat studies demonstrated that POMC mRNA in arcuate nucleus, pituitary and the hypothalamus is diminished and cannot be reversed following insulin treatment (Kim et al., 1999) (Havel et al., 2000). What is more, a-MSH has been reported to have anti-inflammatory effects and has been known to block inflammatory pathways (Abou-Mohamed et al., 1995; Rajora et al., 1997a; Rajora et al., 1997b; Catania et al., 1999; Gatti et al., 2002; Catania et al., 2004). In human dermal fibroblasts α-MSH regulates the expression of IL-8 (Bohm et al., 1999), while in human peripheral blood monocytes and cultured monocytes, α-MSH enhances the expression of the antiinflammatory cytokine IL-10. In septic patients, small concentrations of α-MSH added to LPS-stimulated whole blood samples inhibit TNF-α and IL-1β production and in RAW264.7 mouse macrophages cell line a-
5. Neurotensin (NT) The 13 amino acid neuropeptide NT is primarily produced in the CNS (mainly hypothalamus, amygdala and nucleus accumbens) and in endocrine cells (N cells) of the ileum and jejunum. NT inhibits CNS dopaminergic pathways and promotes growth of various 3
Autonomic Neuroscience: Basic and Clinical 223 (2020) 102610
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DP3DK108224 (AV). AV received funding from the National Rongxiang Xu Foundation. GT received a George and Marie Vergottis Foundation Postdoctoral Fellowship award.
MSH inhibits nitric oxide generation induced by LPS and IFN-γ treatment (Bhardwaj et al., 1996; Taherzadeh et al., 1999; Catania et al., 2000; Star et al., 1995; Mandrika et al., 2001). Moreover, a-MSH suppresses the expression CD86, a major T cell costimulatory molecule, in activated monocytes and M1 classically activated macrophages and promotes the expression of the anti-inflammatory cytokine IL-10 in human peripheral blood monocytes and cultured human monocytes (Bhardwaj et al., 1997). In endothelial cells, α-MSH causes an increase in the release of IL-8, while in stimulated dermal fibroblasts it reduces IL-8 release and in human keratinocytes increases production of IL-10 (Bohm et al., 1999; Kalden et al., 1999; Hartmeyer et al., 1997; Redondo et al., 1998). In murine cutaneous wound healing as well as human burn wounds and hypertrophic scars upregulation of both aMSH and its receptor was observed. Cells positive for a-MSH were epidermal keratinocytes, fibroblasts and inflammatory cells (Muffley et al., 2011). In a rabbit model of corneal wound healing, topical delivery of the C-terminal tripeptide sequence of a-MSH (a-MSH11–13) ameliorated the healing response (Bonfiglio et al., 2006). Furthermore, intraperitoneal injection of a-MSH prior to injury led to significant reduction of leukocytes and mast cells in the granulation tissue of mice 3 and 7 days post-wounding and reduced scar area and collagen fiber organization on day 40 after injury (de Souza et al., 2015). Hence, it appears that a-MSH influences inflammatory pathways and its presence in the skin and involvement in various functions of different skin cell types makes it an attractive target for additional cutaneous diabetic wound healing studies (Bohm and Luger, 2019). A number of other neuropeptides have also been lately implicated in cutaneous wound healing. Somatostatin was shown to exert an inhibitory effect on keratinocyte migration and proliferation both in vitro and on an ex vivo porcine wound healing model (Vockel et al., 2011). Adrenomedullin topically delivered in a sustained-release ointment formation significantly improved wound closure in pressure ulcer patients through acceleration of granulation tissue formation and enhanced neovascularization (Harada et al., 2011). In addition, when used in a combination treatment with its binding protein adrenomedullin also promoted faster wound repair in a rat model of cutaneous healing (Idrovo et al., 2015). Endothelial cell-specific endothelin-1 knockout mice exhibited faster wound healing rates and attenuated fibrosis (Makino et al., 2014) and the role of endothelin-1 in promoting fibrosis is well documented (Rodriguez-Pascual et al., 2014). Using topical gene therapy with the angiogenic neuropeptide secretoneurin in mice resulted in accelerated diabetic wound healing with elevated arteriole and capillary densities in the wounded area (Albrecht-Schgoer et al., 2014). Lastly, treatment of diabetic mice with the neuropeptide relaxin at the wound site lead to increased angiogenesis, vegf mRNA expression and elevated MMP11 levels (Bitto et al., 2013).
References Abou-Mohamed, G., Papapetropoulos, A., Ulrich, D., Catravas, J.D., Tuttle, R.R., Caldwell, R.W., 1995. HP-228, a novel synthetic peptide, inhibits the induction of nitric oxide synthase in vivo but not in vitro. J. Pharmacol. Exp. Ther. 275 (2), 584–591. Ackermann, P.W., Ahmed, M., Kreicbergs, A., 2002. Early nerve regeneration after achilles tendon rupture—a prerequisite for healing? A study in the rat. J. Orthop. Res. 20 (4), 849–856. Adeghate, E., Rashed, H., Rajbandari, S., Singh, J., 2006. Pattern of distribution of calcitonin gene-related peptide in the dorsal root ganglion of animal models of diabetes mellitus. Ann. N. Y. Acad. Sci. 1084, 296–303. Ahlborg, G., Lundberg, J.M., 1996. Exercise-induced changes in neuropeptide Y, noradrenaline and endothelin-1 levels in young people with type I diabetes. Clin. Physiol. 16 (6), 645–655. Albrecht-Schgoer, K., Schgoer, W., Theurl, M., Stanzl, U., Lener, D., Dejaco, D., et al., 2014. Topical secretoneurin gene therapy accelerates diabetic wound healing by interaction between heparan-sulfate proteoglycans and basic FGF. Angiogenesis 17 (1), 27–36. Ansel, J.C., Armstrong, C.A., Song, I., Quinlan, K.L., Olerud, J.E., Caughman, S.W., et al., 1997. Interactions of the skin and nervous system. J Investig. Dermatol. Symp. Proc. 2 (1), 23–26. Arora, S., Pomposelli, F., LoGerfo, F.W., Veves, A., 2002. Cutaneous microcirculation in the neuropathic diabetic foot improves significantly but not completely after successful lower extremity revascularization. J. Vasc. Surg. 35 (3), 501–505. Bedoui, S., Kawamura, N., Straub, R.H., Pabst, R., Yamamura, T., von Horsten, S., 2003. Relevance of neuropeptide Y for the neuroimmune crosstalk. J. Neuroimmunol. 134 (1–2), 1–11. Berelowitz, M., Frohman, L.A., 1982. The role of neurotensin in the regulation of carbohydrate metabolism and in diabetes. Ann. N. Y. Acad. Sci. 400, 150–159. Bhardwaj, R.S., Schwarz, A., Becher, E., Mahnke, K., Aragane, Y., Schwarz, T., et al., 1996. Pro-opiomelanocortin-derived peptides induce IL-10 production in human monocytes. J. Immunol. 156 (7), 2517–2521. Bhardwaj, R., Becher, E., Mahnke, K., Hartmeyer, M., Schwarz, T., Scholzen, T., et al., 1997. Evidence for the differential expression of the functional alpha-melanocytestimulating hormone receptor MC-1 on human monocytes. J. Immunol. 158 (7), 3378–3384. Bitto, A., Irrera, N., Minutoli, L., Calo, M., Lo Cascio, P., Caccia, P., et al., 2013. Relaxin improves multiple markers of wound healing and ameliorates the disturbed healing pattern of genetically diabetic mice. Clin. Sci. 125 (12), 575–585. Bohm, M., Luger, T., 2019. Are melanocortin peptides future therapeutics for cutaneous wound healing? Exp. Dermatol. 28 (3), 219–224. Bohm, M., Schulte, U., Kalden, H., Luger, T.A., 1999. Alpha-melanocyte-stimulating hormone modulates activation of NF-kappa B and AP-1 and secretion of interleukin-8 in human dermal fibroblasts. Ann. N. Y. Acad. Sci. 885, 277–286. Bonfiglio, V., Camillieri, G., Avitabile, T., Leggio, G.M., Drago, F., 2006. Effects of the COOH-terminal tripeptide alpha-MSH(11-13) on corneal epithelial wound healing: role of nitric oxide. Exp. Eye Res. 83 (6), 1366–1372. Boulton, A.J., Scarpello, J.H., Ward, J.D., 1982. Venous oxygenation in the diabetic neuropathic foot: evidence of arteriovenous shunting? Diabetologia 22 (1), 6–8. Bulut, K., Felderbauer, P., Deters, S., Hoeck, K., Schmidt-Choudhury, A., Schmidt, W.E., et al., 2008. Sensory neuropeptides and epithelial cell restitution: the relevance of SPand CGRP-stimulated mast cells. Int. J. Color. Dis. 23 (5), 535–541. Businaro, R., Scaccia, E., Bordin, A., Pagano, F., Corsi, M., Siciliano, C., et al., 2018. Platelet lysate-derived neuropeptide y influences migration and angiogenesis of human adipose tissue-derived stromal cells. Sci. Rep. 8 (1), 14365. Catania, A., Delgado, R., Airaghi, L., Cutuli, M., Garofalo, L., Carlin, A., et al., 1999. Alpha-MSH in systemic inflammation. Central and peripheral actions. Ann. N. Y. Acad. Sci. 885, 183–187. Catania, A., Cutuli, M., Garofalo, L., Airaghi, L., Valenza, F., Lipton, J.M., et al., 2000. Plasma concentrations and anti-L-cytokine effects of alpha-melanocyte stimulating hormone in septic patients. Crit. Care Med. 28 (5), 1403–1407. Catania, A., Gatti, S., Colombo, G., Lipton, J.M., 2004. Targeting melanocortin receptors as a novel strategy to control inflammation. Pharmacol. Rev. 56 (1), 1–29. Chottova Dvorakova, M., Kuncova, J., Pfeil, U., McGregor, G.P., Sviglerova, J., Slavikova, J., et al., 2005. Cardiomyopathy in streptozotocin-induced diabetes involves intraaxonal accumulation of calcitonin gene-related peptide and altered expression of its receptor in rats. Neuroscience 134 (1), 51–58. da Silva, L., Neves, B.M., Moura, L., Cruz, M.T., Carvalho, E., 2011. Neurotensin downregulates the pro-inflammatory properties of skin dendritic cells and increases epidermal growth factor expression. Biochim. Biophys. Acta 1813 (10), 1863–1871. Dallos, A., Kiss, M., Polyanka, H., Dobozy, A., Kemeny, L., Husz, S., 2006. Effects of the neuropeptides substance P, calcitonin gene-related peptide, vasoactive intestinal polypeptide and galanin on the production of nerve growth factor and inflammatory cytokines in cultured human keratinocytes. Neuropeptides 40 (4), 251–263. de Souza, K.S., Cantaruti, T.A., Azevedo Jr., G.M., Galdino, D.A., Rodrigues, C.M., Costa, R.A., et al., 2015. Improved cutaneous wound healing after intraperitoneal injection of alpha-melanocyte-stimulating hormone. Exp. Dermatol. 24 (3), 198–203. DeFronzo, R.A., Ferrannini, E., Alberti, K.G.M.M., Zimmet, P., 2015. International Textbook of Diabetes Mellitus. John Wiley & Sons Inc, Chichester, West Sussex;
7. Summary The functions of diverse neuropeptides have been studied in detail in the brain, but remain underexplored in other densely innervated organs, like the skin. The above studies clearly suggest that the cutaneous nervous system is not only responsible for sensory neurotransmissions to the CNS but plays a crucial role in various skin functions including wound healing. Importantly, they have been associated with impaired diabetic wound healing. More comprehensive investigations of the function of each neuropeptide may assist in determining which neuropeptide is more important in the skin, both in physiological and pathological conditions, and to what extent. Finally, with various positive studies in animal models of wound healing, utilizing neuropeptides for therapeutic interventions of the diabetic foot ulceration could be a promising strategy. Funding This work was supported by the National Institutes of Health Grant 4
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activity by neuropeptides and neurohormones. J. Immunol. 135 (1), 350–354. Kohara, H., Tajima, S., Yamamoto, M., Tabata, Y., 2010. Angiogenesis induced by controlled release of neuropeptide substance P. Biomaterials 31 (33), 8617–8625. Lai, J.P., Douglas, S.D., Ho, W.Z., 1998. Human lymphocytes express substance P and its receptor. J. Neuroimmunol. 86 (1), 80–86. Lai, J.P., Douglas, S.D., Shaheen, F., Pleasure, D.E., Ho, W.Z., 2002. Quantification of substance p mRNA in human immune cells by real-time reverse transcriptase PCR assay. Clin. Diagn. Lab. Immunol. 9 (1), 138–143. Lambrecht, B.N., 2001. Immunologists getting nervous: neuropeptides, dendritic cells and T cell activation. Respir. Res. 2 (3), 133–138. Lambrecht, B.N., Germonpre, P.R., Everaert, E.G., Carro-Muino, I., De Veerman, M., de Felipe, C., et al., 1999. Endogenously produced substance P contributes to lymphocyte proliferation induced by dendritic cells and direct TCR ligation. Eur. J. Immunol. 29 (12), 3815–3825. Leal, E.C., Carvalho, E., Tellechea, A., Kafanas, A., Tecilazich, F., Kearney, C., et al., 2015. Substance P promotes wound healing in diabetes by modulating inflammation and macrophage phenotype. Am. J. Pathol. 185 (6), 1638–1648. Lee, M., Kim, A., Chua Jr., S.C., Obici, S., Wardlaw, S.L., 2007. Transgenic MSH overexpression attenuates the metabolic effects of a high-fat diet. Am. J. Physiol. Endocrinol. Metab. 293 (1), E121–E131. Lemaire, I., 1988. Neurotensin enhances IL-1 production by activated alveolar macrophages. J. Immunol. 140 (9), 2983–2988. Levy, D.M., Karanth, S.S., Springall, D.R., Polak, J.M., 1989. Depletion of cutaneous nerves and neuropeptides in diabetes mellitus: an immunocytochemical study. Diabetologia 32 (7), 427–433. Lindberger, M., Schroder, H.D., Schultzberg, M., Kristensson, K., Persson, A., Ostman, J., et al., 1989. Nerve fibre studies in skin biopsies in peripheral neuropathies. I. Immunohistochemical analysis of neuropeptides in diabetes mellitus. J. Neurol. Sci. 93 (2–3), 289–296. Luger, T.A., 2002. Neuromediators—a crucial component of the skin immune system. J. Dermatol. Sci. 30 (2), 87–93. Maggi, C.A., 1995. Tachykinins and calcitonin gene-related peptide (CGRP) as co-transmitters released from peripheral endings of sensory nerves. Prog. Neurobiol. 45 (1), 1–98. Makino, K., Jinnin, M., Aoi, J., Kajihara, I., Makino, T., Fukushima, S., et al., 2014. Knockout of endothelial cell-derived endothelin-1 attenuates skin fibrosis but accelerates cutaneous wound healing. PLoS One 9 (5), e97972. Mandrika, I., Muceniece, R., Wikberg, J.E., 2001. Effects of melanocortin peptides on lipopolysaccharide/interferon-gamma-induced NF-kappaB DNA binding and nitric oxide production in macrophage-like RAW 264.7 cells: evidence for dual mechanisms of action. Biochem. Pharmacol. 61 (5), 613–621. Matis, W.L., Lavker, R.M., Murphy, G.F., 1990. Substance P induces the expression of an endothelial-leukocyte adhesion molecule by microvascular endothelium. J. Invest. Dermatol. 94 (4), 492–495. Mazurkiewicz, J.E., Corliss, D., Slominski, A., 2000. Spatiotemporal expression, distribution, and processing of POMC and POMC-derived peptides in murine skin. J. Histochem. Cytochem. 48 (7), 905–914. Moura, L.I., Dias, A.M., Suesca, E., Casadiegos, S., Leal, E.C., Fontanilla, M.R., et al., 2014. Neurotensin-loaded collagen dressings reduce inflammation and improve wound healing in diabetic mice. Biochim. Biophys. Acta 1842 (1), 32–43. Mouritzen, M.V., Abourayale, S., Ejaz, R., Ardon, C.B., Carvalho, E., Dalgaard, L.T., et al., 2018. Neurotensin, substance P, and insulin enhance cell migration. J. Pept. Sci. 24 (7), e3093. Muffley, L.A., Zhu, K.Q., Engrav, L.H., Gibran, N.S., Hocking, A.M., 2011. Spatial and temporal localization of the melanocortin 1 receptor and its ligand alpha-melanocytestimulating hormone during cutaneous wound repair. J. Histochem. Cytochem. 59 (3), 278–288. O’Connor, T.M., O’Connell, J., O’Brien, D.I., Goode, T., Bredin, C.P., Shanahan, F., 2004. The role of substance P in inflammatory disease. J. Cell. Physiol. 201 (2), 167–180. Olerud, J.E., Usui, M.L., Seckin, D., Chiu, D.S., Haycox, C.L., Song, I.S., et al., 1999. Neutral endopeptidase expression and distribution in human skin and wounds. J. Invest. Dermatol. 112 (6), 873–881. Oltman, C.L., Davidson, E.P., Coppey, L.J., Kleinschmidt, T.L., Lund, D.D., Adebara, E.T., et al., 2008a. Vascular and neural dysfunction in Zucker diabetic fatty rats: a difficult condition to reverse. Diabetes Obes. Metab. 10 (1), 64–74. Oltman, C.L., Davidson, E.P., Coppey, L.J., Kleinschmidt, T.L., Yorek, M.A., 2009. Treatment of Zucker diabetic fatty rats with AVE7688 improves vascular and neural dysfunction. Diabetes Obes. Metab. 11 (3), 223–233. Park, J.H., Kim, S., Hong, H.S., Son, Y., 2016. Substance P promotes diabetic wound healing by modulating inflammation and restoring cellular activity of mesenchymal stem cells. Wound Repair Regen. 24 (2), 337–348. Pernow, B., 1983. Substance P. Pharmacol. Rev. 35 (2), 85–141. Pradhan, L., Nabzdyk, C., Andersen, N.D., LoGerfo, F.W., Veves, A., 2009. Inflammation and neuropeptides: the connection in diabetic wound healing. Expert Rev. Mol. Med. 11, e2. Pradhan, L., Cai, X., Wu, S., Andersen, N.D., Martin, M., Malek, J., et al., 2011. Gene expression of pro-inflammatory cytokines and neuropeptides in diabetic wound healing. J. Surg. Res. 167 (2), 336–342. Quattrini, C., Jeziorska, M., Malik, R.A., 2004. Small fiber neuropathy in diabetes: clinical consequence and assessment. Int J Low Extrem Wounds 3 (1), 16–21. Rajora, N., Boccoli, G., Burns, D., Sharma, S., Catania, A.P., Lipton, J.M., 1997a. AlphaMSH modulates local and circulating tumor necrosis factor-alpha in experimental brain inflammation. J. Neurosci. 17 (6), 2181–2186. Rajora, N., Boccoli, G., Catania, A., Lipton, J.M., 1997b. Alpha-MSH modulates experimental inflammatory bowel disease. Peptides 18 (3), 381–385. Redondo, P., Garcia-Foncillas, J., Okroujnov, I., Bandres, E., 1998. Alpha-MSH regulates
Hoboken, NJ. Delgado, A.V., McManus, A.T., Chambers, J.P., 2003. Production of tumor necrosis factoralpha, interleukin 1-beta, interleukin 2, and interleukin 6 by rat leukocyte subpopulations after exposure to substance P. Neuropeptides 37 (6), 355–361. Donelan, J., Boucher, W., Papadopoulou, N., Lytinas, M., Papaliodis, D., Dobner, P., et al., 2006. Corticotropin-releasing hormone induces skin vascular permeability through a neurotensin-dependent process. Proc. Natl. Acad. Sci. U. S. A. 103 (20), 7759–7764. Dux, M., Rosta, J., Pinter, S., Santha, P., Jancso, G., 2007. Loss of capsaicin-induced meningeal neurogenic sensory vasodilatation in diabetic rats. Neuroscience 150 (1), 194–201. Edmonds, M.E., Roberts, V.C., Watkins, P.J., 1982. Blood flow in the diabetic neuropathic foot. Diabetologia 22 (1), 9–15. Ekstrand, A.J., Cao, R., Bjorndahl, M., Nystrom, S., Jonsson-Rylander, A.C., Hassani, H., et al., 2003. Deletion of neuropeptide Y (NPY) 2 receptor in mice results in blockage of NPY-induced angiogenesis and delayed wound healing. Proc. Natl. Acad. Sci. U. S. A. 100 (10), 6033–6038. El-Salhy, M., 1998. Neuroendocrine peptides of the gastrointestinal tract of an animal model of human type 2 diabetes mellitus. Acta Diabetol. 35 (4), 194–198. Ericsson, A., Schalling, M., McIntyre, K.R., Lundberg, J.M., Larhammar, D., Seroogy, K., et al., 1987. Detection of neuropeptide Y and its mRNA in megakaryocytes: enhanced levels in certain autoimmune mice. Proc. Natl. Acad. Sci. U. S. A. 84 (16), 5585–5589. Evers, B.M., 2006. Neurotensin and growth of normal and neoplastic tissues. Peptides 27 (10), 2424–2433. Evers, B.M., Bold, R.J., Ehrenfried, J.A., Li, J., Townsend Jr., C.M., Klimpel, G.R., 1994. Characterization of functional neurotensin receptors on human lymphocytes. Surgery 116 (2), 134–139 (discussion 9-40). Felderbauer, P., Bulut, K., Hoeck, K., Deters, S., Schmidt, W.E., Hoffmann, P., 2007. Substance P induces intestinal wound healing via fibroblasts—evidence for a TGFbeta-dependent effect. Int. J. Color. Dis. 22 (12), 1475–1480. Foster, C.A., Mandak, B., Kromer, E., Rot, A., 1992. Calcitonin gene-related peptide is chemotactic for human T lymphocytes. Ann. N. Y. Acad. Sci. 657, 397–404. Gantz, I., Fong, T.M., 2003. The melanocortin system. Am. J. Physiol. Endocrinol. Metab. 284 (3), E468–E474. Garrido, J.J., Arahuetes, R.M., Hernanz, A., De la Fuente, M., 1992. Modulation by neurotensin and neuromedin N of adherence and chemotaxis capacity of murine lymphocytes. Regul. Pept. 41 (1), 27–37. Gatti, S., Colombo, G., Buffa, R., Turcatti, F., Garofalo, L., Carboni, N., et al., 2002. Alphamelanocyte-stimulating hormone protects the allograft in experimental heart transplantation. Transplantation 74 (12), 1678–1684. Goldman, R., Bar-Shavit, Z., Shezen, E., Terry, S., Blumberg, S., 1982. Enhancement of phagocytosis by neurotensin, a newly found biological activity of the neuropeptide. Adv. Exp. Med. Biol. 155, 133–141. Groneberg, D.A., Folkerts, G., Peiser, C., Chung, K.F., Fischer, A., 2004. Neuropeptide Y (NPY). Pulm. Pharmacol. Ther. 17 (4), 173–180. Gross, K.J., Pothoulakis, C., 2007. Role of neuropeptides in inflammatory bowel disease. Inflamm. Bowel Dis. 13 (7), 918–932. Haegerstrand, A., Dalsgaard, C.J., Jonzon, B., Larsson, O., Nilsson, J., 1990. Calcitonin gene-related peptide stimulates proliferation of human endothelial cells. Proc. Natl. Acad. Sci. U. S. A. 87 (9), 3299–3303. Harada, K., Yamahara, K., Ohnishi, S., Otani, K., Kanoh, H., Ishibashi-Ueda, H., et al., 2011. Sustained-release adrenomedullin ointment accelerates wound healing of pressure ulcers. Regul. Pept. 168 (1–3), 21–26. Hartmeyer, M., Scholzen, T., Becher, E., Bhardwaj, R.S., Schwarz, T., Luger, T.A., 1997. Human dermal microvascular endothelial cells express the melanocortin receptor type 1 and produce increased levels of IL-8 upon stimulation with alpha-melanocytestimulating hormone. J. Immunol. 159 (4), 1930–1937. Hartschuh, W., Weihe, E., Reinecke, M., 1983. Peptidergic (neurotensin, VIP, substance P) nerve fibres in the skin. Immunohistochemical evidence of an involvement of neuropeptides in nociception, pruritus and inflammation. Br. J. Dermatol. 109 (Suppl. 25), 14–17. Havel, P.J., Hahn, T.M., Sindelar, D.K., Baskin, D.G., Dallman, M.F., Weigle, D.S., et al., 2000. Effects of streptozotocin-induced diabetes and insulin treatment on the hypothalamic melanocortin system and muscle uncoupling protein 3 expression in rats. Diabetes 49 (2), 244–252. Ho, W.Z., Lai, J.P., Zhu, X.H., Uvaydova, M., Douglas, S.D., 1997. Human monocytes and macrophages express substance P and neurokinin-1 receptor. J. Immunol. 159 (11), 5654–5660. Holzer, P., 1988. Local effector functions of capsaicin-sensitive sensory nerve endings: involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides. Neuroscience 24 (3), 739–768. Idrovo, J.P., Yang, W.L., Jacob, A., Ajakaiye, M.A., Cheyuo, C., Wang, Z., et al., 2015. Combination of adrenomedullin with its binding protein accelerates cutaneous wound healing. PLoS One 10 (3), e0120225. Jing, C., Jia-Han, W., Hong-Xing, Z., 2010. Double-edged effects of neuropeptide substance P on repair of cutaneous trauma. Wound Repair Regen 18 (3), 319–324. Jung, N., Yu, J., Um, J., Dubon, M.J., Park, K.S., 2016. Substance P modulates properties of normal and diabetic dermal fibroblasts. Tissue Eng. Regen. Med. 13 (2), 155–161. Kalden, D.H., Scholzen, T., Brzoska, T., Luger, T.A., 1999. Mechanisms of the antiinflammatory effects of alpha-MSH. Role of transcription factor NF-kappa B and adhesion molecule expression. Ann. N. Y. Acad. Sci. 885, 254–261. Kim, E.M., Grace, M.K., Welch, C.C., Billington, C.J., Levine, A.S., 1999. STZ-induced diabetes decreases and insulin normalizes POMC mRNA in arcuate nucleus and pituitary in rats. Am. J. Phys. 276 (5), R1320–R1326 Pt 2. Kitlinska, J., Lee, E.W., Movafagh, S., Pons, J., Zukowska, Z., 2002. Neuropeptide Yinduced angiogenesis in aging. Peptides 23 (1), 71–77. Koff, W.C., Dunegan, M.A., 1985. Modulation of macrophage-mediated tumoricidal
5
Autonomic Neuroscience: Basic and Clinical 223 (2020) 102610
G. Theocharidis and A. Veves
of calcitonin gene-related peptide in facilitation of wound healing and angiogenesis. Biomed. Pharmacother. 62 (6), 352–359. Tran, M.T., Ritchie, M.H., Lausch, R.N., Oakes, J.E., 2000. Calcitonin gene-related peptide induces IL-8 synthesis in human corneal epithelial cells. J. Immunol. 164 (8), 4307–4312. Um, J., Yu, J., Park, K.S., 2017. Substance P accelerates wound healing in type 2 diabetic mice through endothelial progenitor cell mobilization and Yes-associated protein activation. Mol. Med. Rep. 15 (5), 3035–3040. van Rossum, D., Hanisch, U.K., Quirion, R., 1997. Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors. Neurosci. Biobehav. Rev. 21 (5), 649–678. Vetrugno, R., Liguori, R., Cortelli, P., Montagna, P., 2003. Sympathetic skin response: basic mechanisms and clinical applications. Clin. Auton. Res. 13 (4), 256–270. Vishwanath, R., Mukherjee, R., 1996. Substance P promotes lymphocyte-endothelial cell adhesion preferentially via LFA-1/ICAM-1 interactions. J. Neuroimmunol. 71 (1–2), 163–171. Vockel, M., Pollok, S., Breitenbach, U., Ridderbusch, I., Kreienkamp, H.J., Brandner, J.M., 2011. Somatostatin inhibits cell migration and reduces cell counts of human keratinocytes and delays epidermal wound healing in an ex vivo wound model. PLoS One 6 (5), e19740. Wallengren, J., Badendick, K., Sundler, F., Hakanson, R., Zander, E., 1995. Innervation of the skin of the forearm in diabetic patients: relation to nerve function. Acta Derm. Venereol. 75 (1), 37–42. Wang, F., Millet, I., Bottomly, K., Vignery, A., 1992. Calcitonin gene-related peptide inhibits interleukin 2 production by murine T lymphocytes. J. Biol. Chem. 267 (29), 21052–21057. Weinstock, J.V., Blum, A., Walder, J., Walder, R., 1988. Eosinophils from granulomas in murine schistosomiasis mansoni produce substance P. J. Immunol. 141 (3), 961–966. Wheway, J., Herzog, H., Mackay, F., 2007. NPY and receptors in immune and inflammatory diseases. Curr. Top. Med. Chem. 7 (17), 1743–1752. Wimalawansa, S.J., 1997. Amylin, calcitonin gene-related peptide, calcitonin, and adrenomedullin: a peptide superfamily. Crit. Rev. Neurobiol. 11 (2–3), 167–239. Yamaguchi, M., Kojima, T., Kanekawa, M., Aihara, N., Nogimura, A., Kasai, K., 2004. Neuropeptides stimulate production of interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha in human dental pulp cells. Inflamm. Res. 53 (5), 199–204. Yaraee, R., Ebtekar, M., Ahmadiani, A., Sabahi, F., 2003. Neuropeptides (SP and CGRP) augment pro-inflammatory cytokine production in HSV-infected macrophages. Int. Immunopharmacol. 3 (13–14), 1883–1887. Yorek, M.A., Coppey, L.J., Gellett, J.S., Davidson, E.P., 2004. Sensory nerve innervation of epineurial arterioles of the sciatic nerve containing calcitonin gene-related peptide: effect of streptozotocin-induced diabetes. Exp. Diabesity Res. 5 (3), 187–193. Younan, G., Ogawa, R., Ramirez, M., Helm, D., Dastouri, P., Orgill, D.P., 2010. Analysis of nerve and neuropeptide patterns in vacuum-assisted closure-treated diabetic murine wounds. Plast Reconstr Surg 126 (1), 87–96. Zhang, J.S., Tan, Y.R., Xiang, Y., Luo, Z.Q., Qin, X.Q., 2006. Regulatory peptides modulate adhesion of polymorphonuclear leukocytes to bronchial epithelial cells through regulation of interleukins, ICAM-1 and NF-kappaB/IkappaB. Acta Biochim. Biophys. Sin. Shanghai 38 (2), 119–128. Zheng, Z., Liu, Y., Huang, W., Mo, Y., Lan, Y., Guo, R., et al., 2018. Neurotensin-loaded PLGA/CNC composite nanofiber membranes accelerate diabetic wound healing. Artif. Cells Nanomed. Biotechnol. 1–9. Zhu, F.B., Fang, X.J., Liu, D.W., Shao, Y., Zhang, H.Y., Peng, Y., et al., 2016. Substance P combined with epidermal stem cells promotes wound healing and nerve regeneration in diabetes mellitus. Neural Regen. Res. 11 (3), 493–501. Zukowska, Z., Pons, J., Lee, E.W., Li, L., 2003a. Neuropeptide Y: a new mediator linking sympathetic nerves, blood vessels and immune system? Can. J. Physiol. Pharmacol. 81 (2), 89–94. Zukowska, Z., Grant, D.S., Lee, E.W., 2003b. Neuropeptide Y: a novel mechanism for ischemic angiogenesis. Trends Cardiovasc. Med. 13 (2), 86–92.
interleukin-10 expression by human keratinocytes. Arch. Dermatol. Res. 290 (8), 425–428. Rodriguez-Pascual, F., Busnadiego, O., Gonzalez-Santamaria, J., 2014. The profibrotic role of endothelin-1: is the door still open for the treatment of fibrotic diseases? Life Sci. 118 (2), 156–164. Roosterman, D., Goerge, T., Schneider, S.W., Bunnett, N.W., Steinhoff, M., 2006. Neuronal control of skin function: the skin as a neuroimmunoendocrine organ. Physiol. Rev. 86 (4), 1309–1379. Russwurm, S., Stonans, I., Stonane, E., Wiederhold, M., Luber, A., Zipfel, P.F., et al., 2001. Procalcitonin and CGRP-1 mrna expression in various human tissues. Shock 16 (2), 109–112. Salo, P., Bray, R., Seerattan, R., Reno, C., McDougall, J., Hart, D.A., 2007. Neuropeptides regulate expression of matrix molecule, growth factor and inflammatory mediator mRNA in explants of normal and healing medial collateral ligament. Regul. Pept. 142 (1–2), 1–6. Salo, P.T., Beye, J.A., Seerattan, R.A., Leonard, C.A., Ivie, T.J., Bray, R.C., 2008. Plasticity of peptidergic innervation in healing rabbit medial collateral ligament. Can. J. Surg. 51 (3), 167–172. Schlereth, T., Schukraft, J., Kramer-Best, H.H., Geber, C., Ackermann, T., Birklein, F., 2016. Interaction of calcitonin gene related peptide (CGRP) and substance P (SP) in human skin. Neuropeptides 59, 57–62. Schratzberger, P., Reinisch, N., Prodinger, W.M., Kahler, C.M., Sitte, B.A., Bellmann, R., et al., 1997. Differential chemotactic activities of sensory neuropeptides for human peripheral blood mononuclear cells. J. Immunol. 158 (8), 3895–3901. Scott, J.R., Tamura, R.N., Muangman, P., Isik, F.F., Xie, C., Gibran, N.S., 2008. Topical substance P increases inflammatory cell density in genetically diabetic murine wounds. Wound Repair Regen. 16 (4), 529–533. Seidah, N.G., Benjannet, S., Hamelin, J., Mamarbachi, A.M., Basak, A., Marcinkiewicz, J., et al., 1999. The subtilisin/kexin family of precursor convertases. Emphasis on PC1, PC2/7B2, POMC and the novel enzyme SKI-1. Ann. N. Y. Acad. Sci. 885, 57–74. Service, F.J., Jay, J.M., Rizza, R.A., O’Brien, P.C., Go, V.L., 1986. Neurotensin in diabetes and obesity. Regul. Pept. 14 (1), 85–92. Sheppard, M.C., Bailey, C.J., Flatt, P.R., Swanston-Flatt, S.K., Shennan, K.I., 1985. Immunoreactive neurotensin in spontaneous syndromes of obesity and diabetes in mice. Acta Endocrinol. 108 (4), 532–536. Sheykhzade, M., Dalsgaard, G.T., Johansen, T., Nyborg, N.C., 2000. The effect of longterm streptozotocin-induced diabetes on contractile and relaxation responses of coronary arteries: selective attenuation of CGRP-induced relaxations. Br. J. Pharmacol. 129 (6), 1212–1218. Slominski, A., Wortsman, J., Mazurkiewicz, J.E., Matsuoka, L., Dietrich, J., Lawrence, K., et al., 1993. Detection of proopiomelanocortin-derived antigens in normal and pathologic human skin. J. Lab. Clin. Med. 122 (6), 658–666. Song, J.X., Wang, L.H., Yao, L., Xu, C., Wei, Z.H., Zheng, L.R., 2009. Impaired transient receptor potential vanilloid 1 in streptozotocin-induced diabetic hearts. Int. J. Cardiol. 134 (2), 290–292. Spenny, M.L., Muangman, P., Sullivan, S.R., Bunnett, N.W., Ansel, J.C., Olerud, J.E., et al., 2002. Neutral endopeptidase inhibition in diabetic wound repair. Wound Repair Regen. 10 (5), 295–301. Star, R.A., Rajora, N., Huang, J., Stock, R.C., Catania, A., Lipton, J.M., 1995. Evidence of autocrine modulation of macrophage nitric oxide synthase by alpha-melanocyte-stimulating hormone. Proc. Natl. Acad. Sci. U. S. A. 92 (17), 8016–8020. Strand, F.L., 1999. Neuropeptides: Regulators of Physiological Processes. MIT Press, Cambridge, Mass. Taherzadeh, S., Sharma, S., Chhajlani, V., Gantz, I., Rajora, N., Demitri, M.T., et al., 1999. Alpha-MSH and its receptors in regulation of tumor necrosis factor-alpha production by human monocyte/macrophages. Am. J. Phys. 276 (5), R1289–R1294 Pt 2. Thody, A.J., Ridley, K., Penny, R.J., Chalmers, R., Fisher, C., Shuster, S., 1983. MSH peptides are present in mammalian skin. Peptides 4 (6), 813–816. Toda, M., Suzuki, T., Hosono, K., Kurihara, Y., Kurihara, H., Hayashi, I., et al., 2008. Roles
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Review
Autonomic nerve dysfunction and impaired diabetic wound healing: The role of neuropeptides Georgios Theocharidis, Aristidis Veves
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Joslin-Beth Israel Deaconess Foot Center and The Rongxiang Xu, MD, Center for Regenerative Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
A B S T R A C T
Lower extremity ulcerations represent a major complication in diabetes mellitus and involve multiple physiological factors that lead to impairment of wound healing. Neuropeptides are neuromodulators implicated in various processes including diabetic wound healing. Diabetes causes autonomic and small sensory nerve fibers neuropathy as well as inflammatory dysregulation, which manifest with decreased neuropeptide expression and a disproportion in pro- and anti- inflammatory cytokine response. Therefore to fully understand the contribution of autonomic nerve dysfunction in diabetic wound healing it is crucial to explore the implication of neuropeptides. Here, we will discuss recent studies elucidating the role of specific neuropeptides in wound healing.
1. Introduction The skin is densely innervated by an interconnected system of highly specialized afferent sensory and efferent autonomic nerve fibers (Roosterman et al., 2006; Ansel et al., 1997). Cutaneous autonomic nerve fibers almost completely derive from sympathetic neurons and albeit very effective, they represent only a minority of skin nerve fibers in comparison with sensory nerves. In addition, as opposed to sensory nerves, the distribution of autonomic nerve fibers is restricted to the dermis, innervating blood vessels, lymphatic vessels, erector pili muscles, apocrine and eccrine glands, and hair follicles. Therefore, cutaneous autonomic nerve fibers take part in the modulation of blood circulation, lymphatic function, and skin appendages regulation (Vetrugno et al., 2003). Diabetic patients' skin exhibits motor, sensory and autonomic fiber denervation: sensory neuropathy restricts the sensations of pain, temperature, pressure and others; autonomic denervation leads to arteriovenous shunting, thereby causing vasodilation in small arteries; motor neuropathy induces weakness and wasting of small intrinsic muscles (DeFronzo et al., 2015). Importantly, microcirculation is affected in the diabetic neuropathic foot, mainly through impairment of both endothelium dependent and independent vasodilation (Arora et al., 2002) and peripheral blood flow is elevated and associated with arteriovenous shunting (Edmonds et al., 1982; Boulton et al., 1982). Finally, another consequence of autonomic denervation is sudomotor dysfunction that leads to dry skin and callus formation that play an important role in the development of diabetic foot ulceration. A growing body of studies in both patients and animal models points to a synergistic role of cutaneous nerve fibers and the immune system in
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mediating wound healing. The regulation of the healing response is realized through intricate interplay of components of the local immune and nervous system, which is further regulated via endocrine feedback (Pradhan et al., 2011; Pradhan et al., 2009; Quattrini et al., 2004). Neuropeptides are neuronal short-chain polypeptides that act as signaling molecules affecting numerous processes. Cutaneous nerve fibers and inflammatory cells such as monocytes, macrophages and eosinophils are known to release neuromodulators including cytokines and neuropeptides that regulate the activity of specific cytokine and neuropeptide receptors on a variety of skin cells including mature T and B cells, Langerhans cells, endothelial cells, mast cells, fibroblasts and keratinocytes resulting to the direct activation of G-protein signaling cascades (Roosterman et al., 2006; Luger, 2002). Fig. 1 summarizes how diabetes and neuropeptide expression dysregulation culminate in aberrant wound healing. Neuropeptide Y (NPY), Substance P (SP) and calcitonin gene related peptide (CRGP) are neuropeptides involved in modulating the immune response and wound healing. Further, other neuropeptides such as Melanocyte Stimulating Hormone (MSH) and Neurotensin are also neuromodulators and could potentially participate in impaired diabetic wound healing. These neuropeptides are released from autonomic nerve fibers as well as from cells within the dermis and the epidermis (Pradhan et al., 2011). Furthermore, these neuropeptides regulate the expression and function of numerous cytokines that are implicated and dysregulated in diabetes including IL-1, IL-6, IL-8, IL-10 and TNF-α (Pradhan et al., 2009).
Corresponding author at: Beth Israel Deaconess Medical Center, Palmer 321A, 1 Deaconess Rd, Boston, MA 02215, USA. E-mail address: [email protected] (A. Veves).
https://doi.org/10.1016/j.autneu.2019.102610 Received 15 March 2019; Received in revised form 22 November 2019; Accepted 25 November 2019 1566-0702/ © 2019 Elsevier B.V. All rights reserved.
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Fig. 1. Diabetic neuropathy and neuropeptide dysregulation contribute to lower extremity wound pathogenesis. Diabetes mellitus causes autonomic and small sensory nerve fibers neuropathy in the lower extremity as well as inflammatory dysregulation, which manifest with reduced neuropeptide expression and disproportion in pro- and anti- inflammatory cytokine response. Neuropeptides have a direct effect on leukocytes and further contribute to the cytokine imbalance. Also, cytokines and neuropeptides directly influence various skin cells including fibroblasts, keratinocytes and endothelial cells decreasing their proliferation and resulting in irregular angiogenesis, ECM production and reepithelialization. Reduced neovascularization, reepithelialization and dysregulation in remodeling and granulation tissue deposition, also affected by the abnormal cytokine expression profile, lead to impaired cutaneous wound healing. Adapted from Pradhan et al. (2009)
2. Neuropeptide Y (NPY)
3. Substance P (SP)
NPY is a highly conserved 36 amino acid polypeptide involved in dysregulated healing, and is one of the most abundant neurotransmitters in the mammalian central (CNS) and peripheral nervous system (PNS) (Pradhan et al., 2009). Besides the nerves, other nonneuronal cells have been reported to produce NPY, including megakaryocytes, liver, spleen, and ECs (Ericsson et al., 1987; Strand, 1999). NPY is mostly studied for its impact on the central nervous system, where it induces conservation of energy and counteracts the effects of Leptin. Thus, most of the NPY diabetes studies focus on its CNS effects (Pradhan et al., 2009). In the hypothalamus of both type 1 and type 2 diabetic patients, NPY expression is elevated while in the skin, it is decreased (Ahlborg and Lundberg, 1996; Wallengren et al., 1995; Levy et al., 1989). In a recent study NPY in the plasma of type 2 diabetic patients was found to be increased; however there is no data on dermal NPY expression for these patients. Baseline expression of NPY remains unchanged in a diabetic rabbit model of cutaneous wound healing (Pradhan et al., 2009). In addition, NPY has a pro-angiogenic effect and regulates elements of the innate and adaptive immune system (Pradhan et al., 2009). Specifically, NPY modulates cell migration, cytokine release from macrophages and helper T cells, antigen presentation as well as activation of natural killer cells and antibody production (Wheway et al., 2007; Groneberg et al., 2004; Bedoui et al., 2003). Platelet lysate derived NPY was recently shown to affect migration and angiogenesis potential of human adipose derived stromal cells and co-localized with endothelial markers CD31 and VEGF in difficult to heal wound samples treated with lysate (Businaro et al., 2018). NPY is mostly known to be associated with tendon and cartilage healing, but through its pro-angiogenic receptors NPY-2R and NPY-5R it also influences cutaneous healing (Zukowska et al., 2003a; Salo et al., 2008; Salo et al., 2007; Ackermann et al., 2002). Notably, in genetically modified mice where NPY-2R was deleted, a significant delay in cutaneous wound healing with decreased neovascularization was reported (Ekstrand et al., 2003). The enzyme dipeptidyl peptidase IV (DPP IV) that cleaves NPY into its pro-angiogenic form, which subsequently binds to NPY-2R and NPY-5R receptors, is enriched in aging mice (Zukowska et al., 2003b; Kitlinska et al., 2002). NPY is thus involved in both the inflammatory and angiogenic phases of wound healing. More research is necessary to elucidate the exact role of NPY in diabetic wound healing.
A member of the tachykinin neuropeptide family, SP is an 11 amino acid neuropeptide encoded by the TAC1 gene and is one of the main neuropeptides released by C-nociceptive fibers in response to injury (Olerud et al., 1999). In the last two decades, SP has emerged as a potent modulator of cutaneous wound healing among all healing associated neuropeptides. The pro-angiogenic function of SP has been demonstrated in both in vitro and in vivo experiments and importantly SP has been reported to have a critical role in wound site infiltration of polymorphonuclear leukocytes (Kohara et al., n.d.; Leal et al., 2015). SP also promotes proliferation in fibroblasts (Jung et al., 2016) and inhibits apoptosis through increasing the levels of BCL-2 and proliferating cell nuclear antigen in burn wounds (Jing et al., 2010). Noteworthy, SP has been found to be decreased in skin biopsies from both type 1 and type 2 diabetic patients (Lindberger et al., 1989) and SP mRNA and protein expression is diminished in a rabbit model of type 1 diabetes (Pradhan et al., 2009). Exogenous treatment of diabetic wounds with SP resulted in faster healing in both mice and rats (Leal et al., 2015; Park et al., 2016; Um et al., 2017; Zhu et al., 2016). In addition, topical administration of SP on excisional wounds in a db/db mouse model led to increased leukocyte infiltration compared to saline treatment at the early stages post-wounding, suggesting a role for SP involvement during early inflammation in wound healing (Scott et al., 2008). Moreover, the enzyme that inactivates SP, neutral endopeptidase (NEP) or neprilysin, is increased in diabetes and the use of a NEP inhibitor has been effective in accelerating diabetic wound healing (Spenny et al., 2002). In a rabbit model of diabetic wound-healing, our group has demonstrated reduced SP levels in the diabetic rabbit skin compared to non-diabetic and postwounding, both NPY and SP gene expression is diminished regardless of diabetic status (Pradhan et al., 2009). In endothelial cells, SP is an established vasodilating factor by inducing the production of nitric oxide, consequently enhancing endothelial permeability and leukocyte extravasation into the underlying tissues (Pernow, 1983). It has been recently reported to promote the mobilization of endothelial progenitor cells in the wounded tissue of a murine model of type 2 diabetes and increase the amount of Yes-associated protein expression in the dermis (Um et al., 2017). Furthermore, it acts as a potent chemoattractant for immune cells, promotes elevated expression of endothelial leukocyte adhesion molecule-1 on human microvascular endothelial cells and leukocyte function-associated antigen-1 (LFA-1) on murine endothelial cells and lymphocytes and can raise the levels of an array of 2
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gastrointestinal tissues as well as adrenal gland, hepatocytes and fibroblasts (Evers, 2006). The NT receptors neurotensin receptor 1, neurotensin receptor 2 and sortilin, are found throughout the CNS (Gross and Pothoulakis, 2007). According to different studies, NT may be involved in the pathogenesis of diabetes. Increased levels and total amounts of NT are found in the pancreas of obese (ob/ob) mice and in the intestine of both ob/ob and diabetic (db/db) mice (Sheppard et al., 1985). Similarly, insulin mediates NT concentrations in the pancreas, with high NT levels correlating with insulin deficiency in ob/ob and db/db mice (Berelowitz and Frohman, 1982). Nevertheless, in another study, NT expression was comparable between lean and diabetic mice. In addition, research in human patients did not reveal any difference in NT amounts between healthy nondiabetic subjects and lean and obese diabetic patients either pre- or postprandially (El-Salhy, 1998; Service et al., 1986). NT has been reported to affect wound healing by modulating cell functions of both innate and adaptive immunity, namely macrophages and T cells (Goldman et al., 1982; Koff and Dunegan, 1985; Lemaire, 1988; Garrido et al., 1992; Evers et al., 1994). NT expressing nerve fibers and NT mRNA are both present in the skin. Cutaneous NT activates skin mast cells causing secretion of histamine (Hartschuh et al., 1983; Donelan et al., 2006). In a recent study, in vitro treatment of keratinocytes and T cells with NT was shown to enhance migration and reduced the expression of TNF-α and IL-8. Interestingly, co-stimulation with SP led to decreased migratory capacity, while the angiogenesis in HUVEC cells was elevated (Mouritzen et al., 2018). NT also has an effect on cutaneous dendritic cells through downregulation of activation of inflammatory pathways JNK and NF-κB and reduction of expression of inflammatory cytokines IL-6, TNF-α and IL-10 (da Silva et al., 2011). Noteworthy, in two different mouse diabetic wound healing studies, delivery of NT with specially designed biomaterials enhanced wound closure. Collagen dressings functionalized with NT reduced inflammation and accelerated wound healing (Moura et al., 2014), whereas PLGA membranes loaded with NT also resulted in more rapid wound healing and decrease in inflammatory cytokine expression (Zheng et al., 2018). Therefore, topical delivery of NT could potentially be a promising treatment for diabetic foot ulcers.
inflammation linked cytokines including TGF-beta, TNF-α, IL-1β, IL-2, IL-8, IL-6 from dendritic and T cells, neutrophils, macrophages and fibroblasts (Matis et al., 1990; Vishwanath and Mukherjee, 1996; Delgado et al., 2003; Ho et al., 1997; Lai et al., 1998; Lai et al., 2002; Lambrecht, 2001; Lambrecht et al., 1999; Weinstock et al., 1988; O'Connor et al., 2004; Schratzberger et al., 1997; Bulut et al., 2008; Felderbauer et al., 2007). Hence by generating a pro-inflammatory environment within the wound site SP plays a crucial role in the inflammatory and angiogenic phases of wound healing. 4. Calcitonin gene related peptide (CGRP) CGRP is a 37 amino acid neuropeptide produced by an alternative splicing of the calcitonin gene (Wimalawansa, 1997). Just like NPY, CGRP is present in both the CNS and the PNS. In the PNS, CGRP is stored and released together with SP from capsaicin sensitive peripheral afferent neurons and is also a potent vasodilator (van Rossum et al., 1997; Holzer, 1988; Maggi, 1995). Notably, co-application of CGRP and SP to human skin induced long lasting vasodilation in a dose-dependent manner highlighting a synergistic effect of the two neuropeptides (Schlereth et al., 2016). Comparable to NPY, CGRP is found to be expressed outside the neurons in diverse organs such as the kidneys, liver, lungs and prostate (Russwurm et al., 2001). In peripheral tissues, CGRP receptors exist in the heart, liver, spleen, skeletal muscle, lungs, lymphocytes and the vasculature (van Rossum et al., 1997). A marked reduction of CGRP reactive fibers has been reported in the dermis of type 1 and type 2 diabetic patients (Lindberger et al., 1989). Diabetes has been shown to decrease the levels of CGRP in murine hearts, limit CGRP-mediated vasodilation in rats and diminish both CGRP and CGRP receptor expression in a rat model of diabetic cardiomyopathy (Chottova Dvorakova et al., 2005; Yorek et al., 2004; Oltman et al., 2008a; Oltman et al., 2009; Sheykhzade et al., 2000; Song et al., 2009; Dux et al., 2007; Adeghate et al., 2006). CGRP is also involved in the wound healing process by promoting neovascularization through elevated VEGF secretion from wound site cells and triggering the cAMP pathway (Toda et al., 2008; Haegerstrand et al., 1990). Moreover, CGRP induces release of both IL-1α and IL-8 in keratinocytes, IL-8 in the corneal epithelium, IL-1α, IL-8 and ICAM-1 in airway epithelium, IL-1β and TNF-α in macrophages, IL-1β, IL-6 and TNF-α in dental pulp fibroblasts, and acts as a chemoattractant for T cells, mediates lymphocyte proliferation and inhibits IL-2 expression (Zhang et al., 2006; Tran et al., 2000; Dallos et al., 2006; Yamaguchi et al., 2004; Yaraee et al., 2003; Wang et al., 1992; Foster et al., 1992). In animal models of diabetes CGRP was also decreased in tissues such as the heart and the dorsal root ganglion, but not much is known about its cutaneous expression (Oltman et al., 2008a; Oltman et al., 2009; Sheykhzade et al., 2000). In a recent study, vacuum-assisted treated wounds in a diabetic mouse model exhibited a significant increase in dermal and epidermal nerve fiber densities and in SP, CGRP, and nerve growth factor expression. In particular, the cyclical treatment mode correlated with the largest enhancement in granulation tissue production, and a slightly quicker wound closure rate (Younan et al., 2010). In CGRP-null mice (CGRP−/−), neovascularization and wound healing were impaired in comparison with control wild-type mice, and a reduction in the levels of VEGF from the wound granulation tissue was demonstrated (Toda et al., 2008). These findings indicate that the association of CGRP in wound healing is modulated through its impact on angiogenesis. Thus, exogenous CGRP addition may promote enhanced angiogenesis and wound healing.
6. Alpha-melanocyte-stimulating hormone (a-MSH) a-MSH is a 13 amino acid hormone and neuropeptide and belongs to the family of melanocortins, a number of structurally related peptides that not only participate in the regulation of pigmentation and cortisol expression but also modulate food intake, energy homeostasis, exocrine gland function, and inflammatory response (Gantz and Fong, 2003). aMSH is a proteolytic cleavage product of proopiomelanocortin (POMC) and is predominantly released from the pars intermedia region of the pituitary gland (Seidah et al., 1999). Noteworthy, significant amounts of a-MSH are present in the human skin (Thody et al., 1983; Slominski et al., 1993; Mazurkiewicz et al., 2000). A number of different cutaneous cell types including keratinocytes, fibroblasts, melanocytes and endothelial cells generate a-MSH and express melanocortin receptors (MCRs). Long-term activation of a-MSH decreases body weight and improves glucose metabolism in a model of diet-induced obesity (Lee et al., 2007). Two diabetic rat studies demonstrated that POMC mRNA in arcuate nucleus, pituitary and the hypothalamus is diminished and cannot be reversed following insulin treatment (Kim et al., 1999) (Havel et al., 2000). What is more, a-MSH has been reported to have anti-inflammatory effects and has been known to block inflammatory pathways (Abou-Mohamed et al., 1995; Rajora et al., 1997a; Rajora et al., 1997b; Catania et al., 1999; Gatti et al., 2002; Catania et al., 2004). In human dermal fibroblasts α-MSH regulates the expression of IL-8 (Bohm et al., 1999), while in human peripheral blood monocytes and cultured monocytes, α-MSH enhances the expression of the antiinflammatory cytokine IL-10. In septic patients, small concentrations of α-MSH added to LPS-stimulated whole blood samples inhibit TNF-α and IL-1β production and in RAW264.7 mouse macrophages cell line a-
5. Neurotensin (NT) The 13 amino acid neuropeptide NT is primarily produced in the CNS (mainly hypothalamus, amygdala and nucleus accumbens) and in endocrine cells (N cells) of the ileum and jejunum. NT inhibits CNS dopaminergic pathways and promotes growth of various 3
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DP3DK108224 (AV). AV received funding from the National Rongxiang Xu Foundation. GT received a George and Marie Vergottis Foundation Postdoctoral Fellowship award.
MSH inhibits nitric oxide generation induced by LPS and IFN-γ treatment (Bhardwaj et al., 1996; Taherzadeh et al., 1999; Catania et al., 2000; Star et al., 1995; Mandrika et al., 2001). Moreover, a-MSH suppresses the expression CD86, a major T cell costimulatory molecule, in activated monocytes and M1 classically activated macrophages and promotes the expression of the anti-inflammatory cytokine IL-10 in human peripheral blood monocytes and cultured human monocytes (Bhardwaj et al., 1997). In endothelial cells, α-MSH causes an increase in the release of IL-8, while in stimulated dermal fibroblasts it reduces IL-8 release and in human keratinocytes increases production of IL-10 (Bohm et al., 1999; Kalden et al., 1999; Hartmeyer et al., 1997; Redondo et al., 1998). In murine cutaneous wound healing as well as human burn wounds and hypertrophic scars upregulation of both aMSH and its receptor was observed. Cells positive for a-MSH were epidermal keratinocytes, fibroblasts and inflammatory cells (Muffley et al., 2011). In a rabbit model of corneal wound healing, topical delivery of the C-terminal tripeptide sequence of a-MSH (a-MSH11–13) ameliorated the healing response (Bonfiglio et al., 2006). Furthermore, intraperitoneal injection of a-MSH prior to injury led to significant reduction of leukocytes and mast cells in the granulation tissue of mice 3 and 7 days post-wounding and reduced scar area and collagen fiber organization on day 40 after injury (de Souza et al., 2015). Hence, it appears that a-MSH influences inflammatory pathways and its presence in the skin and involvement in various functions of different skin cell types makes it an attractive target for additional cutaneous diabetic wound healing studies (Bohm and Luger, 2019). A number of other neuropeptides have also been lately implicated in cutaneous wound healing. Somatostatin was shown to exert an inhibitory effect on keratinocyte migration and proliferation both in vitro and on an ex vivo porcine wound healing model (Vockel et al., 2011). Adrenomedullin topically delivered in a sustained-release ointment formation significantly improved wound closure in pressure ulcer patients through acceleration of granulation tissue formation and enhanced neovascularization (Harada et al., 2011). In addition, when used in a combination treatment with its binding protein adrenomedullin also promoted faster wound repair in a rat model of cutaneous healing (Idrovo et al., 2015). Endothelial cell-specific endothelin-1 knockout mice exhibited faster wound healing rates and attenuated fibrosis (Makino et al., 2014) and the role of endothelin-1 in promoting fibrosis is well documented (Rodriguez-Pascual et al., 2014). Using topical gene therapy with the angiogenic neuropeptide secretoneurin in mice resulted in accelerated diabetic wound healing with elevated arteriole and capillary densities in the wounded area (Albrecht-Schgoer et al., 2014). Lastly, treatment of diabetic mice with the neuropeptide relaxin at the wound site lead to increased angiogenesis, vegf mRNA expression and elevated MMP11 levels (Bitto et al., 2013).
References Abou-Mohamed, G., Papapetropoulos, A., Ulrich, D., Catravas, J.D., Tuttle, R.R., Caldwell, R.W., 1995. HP-228, a novel synthetic peptide, inhibits the induction of nitric oxide synthase in vivo but not in vitro. J. Pharmacol. Exp. Ther. 275 (2), 584–591. Ackermann, P.W., Ahmed, M., Kreicbergs, A., 2002. Early nerve regeneration after achilles tendon rupture—a prerequisite for healing? A study in the rat. J. Orthop. Res. 20 (4), 849–856. Adeghate, E., Rashed, H., Rajbandari, S., Singh, J., 2006. Pattern of distribution of calcitonin gene-related peptide in the dorsal root ganglion of animal models of diabetes mellitus. Ann. N. Y. Acad. Sci. 1084, 296–303. Ahlborg, G., Lundberg, J.M., 1996. Exercise-induced changes in neuropeptide Y, noradrenaline and endothelin-1 levels in young people with type I diabetes. Clin. Physiol. 16 (6), 645–655. Albrecht-Schgoer, K., Schgoer, W., Theurl, M., Stanzl, U., Lener, D., Dejaco, D., et al., 2014. Topical secretoneurin gene therapy accelerates diabetic wound healing by interaction between heparan-sulfate proteoglycans and basic FGF. Angiogenesis 17 (1), 27–36. Ansel, J.C., Armstrong, C.A., Song, I., Quinlan, K.L., Olerud, J.E., Caughman, S.W., et al., 1997. Interactions of the skin and nervous system. J Investig. Dermatol. Symp. Proc. 2 (1), 23–26. Arora, S., Pomposelli, F., LoGerfo, F.W., Veves, A., 2002. Cutaneous microcirculation in the neuropathic diabetic foot improves significantly but not completely after successful lower extremity revascularization. J. Vasc. Surg. 35 (3), 501–505. Bedoui, S., Kawamura, N., Straub, R.H., Pabst, R., Yamamura, T., von Horsten, S., 2003. Relevance of neuropeptide Y for the neuroimmune crosstalk. J. Neuroimmunol. 134 (1–2), 1–11. Berelowitz, M., Frohman, L.A., 1982. The role of neurotensin in the regulation of carbohydrate metabolism and in diabetes. Ann. N. Y. Acad. Sci. 400, 150–159. Bhardwaj, R.S., Schwarz, A., Becher, E., Mahnke, K., Aragane, Y., Schwarz, T., et al., 1996. Pro-opiomelanocortin-derived peptides induce IL-10 production in human monocytes. J. Immunol. 156 (7), 2517–2521. Bhardwaj, R., Becher, E., Mahnke, K., Hartmeyer, M., Schwarz, T., Scholzen, T., et al., 1997. Evidence for the differential expression of the functional alpha-melanocytestimulating hormone receptor MC-1 on human monocytes. J. Immunol. 158 (7), 3378–3384. Bitto, A., Irrera, N., Minutoli, L., Calo, M., Lo Cascio, P., Caccia, P., et al., 2013. Relaxin improves multiple markers of wound healing and ameliorates the disturbed healing pattern of genetically diabetic mice. Clin. Sci. 125 (12), 575–585. Bohm, M., Luger, T., 2019. Are melanocortin peptides future therapeutics for cutaneous wound healing? Exp. Dermatol. 28 (3), 219–224. Bohm, M., Schulte, U., Kalden, H., Luger, T.A., 1999. Alpha-melanocyte-stimulating hormone modulates activation of NF-kappa B and AP-1 and secretion of interleukin-8 in human dermal fibroblasts. Ann. N. Y. Acad. Sci. 885, 277–286. Bonfiglio, V., Camillieri, G., Avitabile, T., Leggio, G.M., Drago, F., 2006. Effects of the COOH-terminal tripeptide alpha-MSH(11-13) on corneal epithelial wound healing: role of nitric oxide. Exp. Eye Res. 83 (6), 1366–1372. Boulton, A.J., Scarpello, J.H., Ward, J.D., 1982. Venous oxygenation in the diabetic neuropathic foot: evidence of arteriovenous shunting? Diabetologia 22 (1), 6–8. Bulut, K., Felderbauer, P., Deters, S., Hoeck, K., Schmidt-Choudhury, A., Schmidt, W.E., et al., 2008. Sensory neuropeptides and epithelial cell restitution: the relevance of SPand CGRP-stimulated mast cells. Int. J. Color. Dis. 23 (5), 535–541. Businaro, R., Scaccia, E., Bordin, A., Pagano, F., Corsi, M., Siciliano, C., et al., 2018. Platelet lysate-derived neuropeptide y influences migration and angiogenesis of human adipose tissue-derived stromal cells. Sci. Rep. 8 (1), 14365. Catania, A., Delgado, R., Airaghi, L., Cutuli, M., Garofalo, L., Carlin, A., et al., 1999. Alpha-MSH in systemic inflammation. Central and peripheral actions. Ann. N. Y. Acad. Sci. 885, 183–187. Catania, A., Cutuli, M., Garofalo, L., Airaghi, L., Valenza, F., Lipton, J.M., et al., 2000. Plasma concentrations and anti-L-cytokine effects of alpha-melanocyte stimulating hormone in septic patients. Crit. Care Med. 28 (5), 1403–1407. Catania, A., Gatti, S., Colombo, G., Lipton, J.M., 2004. Targeting melanocortin receptors as a novel strategy to control inflammation. Pharmacol. Rev. 56 (1), 1–29. Chottova Dvorakova, M., Kuncova, J., Pfeil, U., McGregor, G.P., Sviglerova, J., Slavikova, J., et al., 2005. Cardiomyopathy in streptozotocin-induced diabetes involves intraaxonal accumulation of calcitonin gene-related peptide and altered expression of its receptor in rats. Neuroscience 134 (1), 51–58. da Silva, L., Neves, B.M., Moura, L., Cruz, M.T., Carvalho, E., 2011. Neurotensin downregulates the pro-inflammatory properties of skin dendritic cells and increases epidermal growth factor expression. Biochim. Biophys. Acta 1813 (10), 1863–1871. Dallos, A., Kiss, M., Polyanka, H., Dobozy, A., Kemeny, L., Husz, S., 2006. Effects of the neuropeptides substance P, calcitonin gene-related peptide, vasoactive intestinal polypeptide and galanin on the production of nerve growth factor and inflammatory cytokines in cultured human keratinocytes. Neuropeptides 40 (4), 251–263. de Souza, K.S., Cantaruti, T.A., Azevedo Jr., G.M., Galdino, D.A., Rodrigues, C.M., Costa, R.A., et al., 2015. Improved cutaneous wound healing after intraperitoneal injection of alpha-melanocyte-stimulating hormone. Exp. Dermatol. 24 (3), 198–203. DeFronzo, R.A., Ferrannini, E., Alberti, K.G.M.M., Zimmet, P., 2015. International Textbook of Diabetes Mellitus. John Wiley & Sons Inc, Chichester, West Sussex;
7. Summary The functions of diverse neuropeptides have been studied in detail in the brain, but remain underexplored in other densely innervated organs, like the skin. The above studies clearly suggest that the cutaneous nervous system is not only responsible for sensory neurotransmissions to the CNS but plays a crucial role in various skin functions including wound healing. Importantly, they have been associated with impaired diabetic wound healing. More comprehensive investigations of the function of each neuropeptide may assist in determining which neuropeptide is more important in the skin, both in physiological and pathological conditions, and to what extent. Finally, with various positive studies in animal models of wound healing, utilizing neuropeptides for therapeutic interventions of the diabetic foot ulceration could be a promising strategy. Funding This work was supported by the National Institutes of Health Grant 4
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activity by neuropeptides and neurohormones. J. Immunol. 135 (1), 350–354. Kohara, H., Tajima, S., Yamamoto, M., Tabata, Y., 2010. Angiogenesis induced by controlled release of neuropeptide substance P. Biomaterials 31 (33), 8617–8625. Lai, J.P., Douglas, S.D., Ho, W.Z., 1998. Human lymphocytes express substance P and its receptor. J. Neuroimmunol. 86 (1), 80–86. Lai, J.P., Douglas, S.D., Shaheen, F., Pleasure, D.E., Ho, W.Z., 2002. Quantification of substance p mRNA in human immune cells by real-time reverse transcriptase PCR assay. Clin. Diagn. Lab. Immunol. 9 (1), 138–143. Lambrecht, B.N., 2001. Immunologists getting nervous: neuropeptides, dendritic cells and T cell activation. Respir. Res. 2 (3), 133–138. Lambrecht, B.N., Germonpre, P.R., Everaert, E.G., Carro-Muino, I., De Veerman, M., de Felipe, C., et al., 1999. Endogenously produced substance P contributes to lymphocyte proliferation induced by dendritic cells and direct TCR ligation. Eur. J. Immunol. 29 (12), 3815–3825. Leal, E.C., Carvalho, E., Tellechea, A., Kafanas, A., Tecilazich, F., Kearney, C., et al., 2015. Substance P promotes wound healing in diabetes by modulating inflammation and macrophage phenotype. Am. J. Pathol. 185 (6), 1638–1648. Lee, M., Kim, A., Chua Jr., S.C., Obici, S., Wardlaw, S.L., 2007. Transgenic MSH overexpression attenuates the metabolic effects of a high-fat diet. Am. J. Physiol. Endocrinol. Metab. 293 (1), E121–E131. Lemaire, I., 1988. Neurotensin enhances IL-1 production by activated alveolar macrophages. J. Immunol. 140 (9), 2983–2988. Levy, D.M., Karanth, S.S., Springall, D.R., Polak, J.M., 1989. Depletion of cutaneous nerves and neuropeptides in diabetes mellitus: an immunocytochemical study. Diabetologia 32 (7), 427–433. Lindberger, M., Schroder, H.D., Schultzberg, M., Kristensson, K., Persson, A., Ostman, J., et al., 1989. Nerve fibre studies in skin biopsies in peripheral neuropathies. I. Immunohistochemical analysis of neuropeptides in diabetes mellitus. J. Neurol. Sci. 93 (2–3), 289–296. Luger, T.A., 2002. Neuromediators—a crucial component of the skin immune system. J. Dermatol. Sci. 30 (2), 87–93. Maggi, C.A., 1995. Tachykinins and calcitonin gene-related peptide (CGRP) as co-transmitters released from peripheral endings of sensory nerves. Prog. Neurobiol. 45 (1), 1–98. Makino, K., Jinnin, M., Aoi, J., Kajihara, I., Makino, T., Fukushima, S., et al., 2014. Knockout of endothelial cell-derived endothelin-1 attenuates skin fibrosis but accelerates cutaneous wound healing. PLoS One 9 (5), e97972. Mandrika, I., Muceniece, R., Wikberg, J.E., 2001. Effects of melanocortin peptides on lipopolysaccharide/interferon-gamma-induced NF-kappaB DNA binding and nitric oxide production in macrophage-like RAW 264.7 cells: evidence for dual mechanisms of action. Biochem. Pharmacol. 61 (5), 613–621. Matis, W.L., Lavker, R.M., Murphy, G.F., 1990. Substance P induces the expression of an endothelial-leukocyte adhesion molecule by microvascular endothelium. J. Invest. Dermatol. 94 (4), 492–495. Mazurkiewicz, J.E., Corliss, D., Slominski, A., 2000. Spatiotemporal expression, distribution, and processing of POMC and POMC-derived peptides in murine skin. J. Histochem. Cytochem. 48 (7), 905–914. Moura, L.I., Dias, A.M., Suesca, E., Casadiegos, S., Leal, E.C., Fontanilla, M.R., et al., 2014. Neurotensin-loaded collagen dressings reduce inflammation and improve wound healing in diabetic mice. Biochim. Biophys. Acta 1842 (1), 32–43. Mouritzen, M.V., Abourayale, S., Ejaz, R., Ardon, C.B., Carvalho, E., Dalgaard, L.T., et al., 2018. Neurotensin, substance P, and insulin enhance cell migration. J. Pept. Sci. 24 (7), e3093. Muffley, L.A., Zhu, K.Q., Engrav, L.H., Gibran, N.S., Hocking, A.M., 2011. Spatial and temporal localization of the melanocortin 1 receptor and its ligand alpha-melanocytestimulating hormone during cutaneous wound repair. J. Histochem. Cytochem. 59 (3), 278–288. O’Connor, T.M., O’Connell, J., O’Brien, D.I., Goode, T., Bredin, C.P., Shanahan, F., 2004. The role of substance P in inflammatory disease. J. Cell. Physiol. 201 (2), 167–180. Olerud, J.E., Usui, M.L., Seckin, D., Chiu, D.S., Haycox, C.L., Song, I.S., et al., 1999. Neutral endopeptidase expression and distribution in human skin and wounds. J. Invest. Dermatol. 112 (6), 873–881. Oltman, C.L., Davidson, E.P., Coppey, L.J., Kleinschmidt, T.L., Lund, D.D., Adebara, E.T., et al., 2008a. Vascular and neural dysfunction in Zucker diabetic fatty rats: a difficult condition to reverse. Diabetes Obes. Metab. 10 (1), 64–74. Oltman, C.L., Davidson, E.P., Coppey, L.J., Kleinschmidt, T.L., Yorek, M.A., 2009. Treatment of Zucker diabetic fatty rats with AVE7688 improves vascular and neural dysfunction. Diabetes Obes. Metab. 11 (3), 223–233. Park, J.H., Kim, S., Hong, H.S., Son, Y., 2016. Substance P promotes diabetic wound healing by modulating inflammation and restoring cellular activity of mesenchymal stem cells. Wound Repair Regen. 24 (2), 337–348. Pernow, B., 1983. Substance P. Pharmacol. Rev. 35 (2), 85–141. Pradhan, L., Nabzdyk, C., Andersen, N.D., LoGerfo, F.W., Veves, A., 2009. Inflammation and neuropeptides: the connection in diabetic wound healing. Expert Rev. Mol. Med. 11, e2. Pradhan, L., Cai, X., Wu, S., Andersen, N.D., Martin, M., Malek, J., et al., 2011. Gene expression of pro-inflammatory cytokines and neuropeptides in diabetic wound healing. J. Surg. Res. 167 (2), 336–342. Quattrini, C., Jeziorska, M., Malik, R.A., 2004. Small fiber neuropathy in diabetes: clinical consequence and assessment. Int J Low Extrem Wounds 3 (1), 16–21. Rajora, N., Boccoli, G., Burns, D., Sharma, S., Catania, A.P., Lipton, J.M., 1997a. AlphaMSH modulates local and circulating tumor necrosis factor-alpha in experimental brain inflammation. J. Neurosci. 17 (6), 2181–2186. Rajora, N., Boccoli, G., Catania, A., Lipton, J.M., 1997b. Alpha-MSH modulates experimental inflammatory bowel disease. Peptides 18 (3), 381–385. Redondo, P., Garcia-Foncillas, J., Okroujnov, I., Bandres, E., 1998. Alpha-MSH regulates
Hoboken, NJ. Delgado, A.V., McManus, A.T., Chambers, J.P., 2003. Production of tumor necrosis factoralpha, interleukin 1-beta, interleukin 2, and interleukin 6 by rat leukocyte subpopulations after exposure to substance P. Neuropeptides 37 (6), 355–361. Donelan, J., Boucher, W., Papadopoulou, N., Lytinas, M., Papaliodis, D., Dobner, P., et al., 2006. Corticotropin-releasing hormone induces skin vascular permeability through a neurotensin-dependent process. Proc. Natl. Acad. Sci. U. S. A. 103 (20), 7759–7764. Dux, M., Rosta, J., Pinter, S., Santha, P., Jancso, G., 2007. Loss of capsaicin-induced meningeal neurogenic sensory vasodilatation in diabetic rats. Neuroscience 150 (1), 194–201. Edmonds, M.E., Roberts, V.C., Watkins, P.J., 1982. Blood flow in the diabetic neuropathic foot. Diabetologia 22 (1), 9–15. Ekstrand, A.J., Cao, R., Bjorndahl, M., Nystrom, S., Jonsson-Rylander, A.C., Hassani, H., et al., 2003. Deletion of neuropeptide Y (NPY) 2 receptor in mice results in blockage of NPY-induced angiogenesis and delayed wound healing. Proc. Natl. Acad. Sci. U. S. A. 100 (10), 6033–6038. El-Salhy, M., 1998. Neuroendocrine peptides of the gastrointestinal tract of an animal model of human type 2 diabetes mellitus. Acta Diabetol. 35 (4), 194–198. Ericsson, A., Schalling, M., McIntyre, K.R., Lundberg, J.M., Larhammar, D., Seroogy, K., et al., 1987. Detection of neuropeptide Y and its mRNA in megakaryocytes: enhanced levels in certain autoimmune mice. Proc. Natl. Acad. Sci. U. S. A. 84 (16), 5585–5589. Evers, B.M., 2006. Neurotensin and growth of normal and neoplastic tissues. Peptides 27 (10), 2424–2433. Evers, B.M., Bold, R.J., Ehrenfried, J.A., Li, J., Townsend Jr., C.M., Klimpel, G.R., 1994. Characterization of functional neurotensin receptors on human lymphocytes. Surgery 116 (2), 134–139 (discussion 9-40). Felderbauer, P., Bulut, K., Hoeck, K., Deters, S., Schmidt, W.E., Hoffmann, P., 2007. Substance P induces intestinal wound healing via fibroblasts—evidence for a TGFbeta-dependent effect. Int. J. Color. Dis. 22 (12), 1475–1480. Foster, C.A., Mandak, B., Kromer, E., Rot, A., 1992. Calcitonin gene-related peptide is chemotactic for human T lymphocytes. Ann. N. Y. Acad. Sci. 657, 397–404. Gantz, I., Fong, T.M., 2003. The melanocortin system. Am. J. Physiol. Endocrinol. Metab. 284 (3), E468–E474. Garrido, J.J., Arahuetes, R.M., Hernanz, A., De la Fuente, M., 1992. Modulation by neurotensin and neuromedin N of adherence and chemotaxis capacity of murine lymphocytes. Regul. Pept. 41 (1), 27–37. Gatti, S., Colombo, G., Buffa, R., Turcatti, F., Garofalo, L., Carboni, N., et al., 2002. Alphamelanocyte-stimulating hormone protects the allograft in experimental heart transplantation. Transplantation 74 (12), 1678–1684. Goldman, R., Bar-Shavit, Z., Shezen, E., Terry, S., Blumberg, S., 1982. Enhancement of phagocytosis by neurotensin, a newly found biological activity of the neuropeptide. Adv. Exp. Med. Biol. 155, 133–141. Groneberg, D.A., Folkerts, G., Peiser, C., Chung, K.F., Fischer, A., 2004. Neuropeptide Y (NPY). Pulm. Pharmacol. Ther. 17 (4), 173–180. Gross, K.J., Pothoulakis, C., 2007. Role of neuropeptides in inflammatory bowel disease. Inflamm. Bowel Dis. 13 (7), 918–932. Haegerstrand, A., Dalsgaard, C.J., Jonzon, B., Larsson, O., Nilsson, J., 1990. Calcitonin gene-related peptide stimulates proliferation of human endothelial cells. Proc. Natl. Acad. Sci. U. S. A. 87 (9), 3299–3303. Harada, K., Yamahara, K., Ohnishi, S., Otani, K., Kanoh, H., Ishibashi-Ueda, H., et al., 2011. Sustained-release adrenomedullin ointment accelerates wound healing of pressure ulcers. Regul. Pept. 168 (1–3), 21–26. Hartmeyer, M., Scholzen, T., Becher, E., Bhardwaj, R.S., Schwarz, T., Luger, T.A., 1997. Human dermal microvascular endothelial cells express the melanocortin receptor type 1 and produce increased levels of IL-8 upon stimulation with alpha-melanocytestimulating hormone. J. Immunol. 159 (4), 1930–1937. Hartschuh, W., Weihe, E., Reinecke, M., 1983. Peptidergic (neurotensin, VIP, substance P) nerve fibres in the skin. Immunohistochemical evidence of an involvement of neuropeptides in nociception, pruritus and inflammation. Br. J. Dermatol. 109 (Suppl. 25), 14–17. Havel, P.J., Hahn, T.M., Sindelar, D.K., Baskin, D.G., Dallman, M.F., Weigle, D.S., et al., 2000. Effects of streptozotocin-induced diabetes and insulin treatment on the hypothalamic melanocortin system and muscle uncoupling protein 3 expression in rats. Diabetes 49 (2), 244–252. Ho, W.Z., Lai, J.P., Zhu, X.H., Uvaydova, M., Douglas, S.D., 1997. Human monocytes and macrophages express substance P and neurokinin-1 receptor. J. Immunol. 159 (11), 5654–5660. Holzer, P., 1988. Local effector functions of capsaicin-sensitive sensory nerve endings: involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides. Neuroscience 24 (3), 739–768. Idrovo, J.P., Yang, W.L., Jacob, A., Ajakaiye, M.A., Cheyuo, C., Wang, Z., et al., 2015. Combination of adrenomedullin with its binding protein accelerates cutaneous wound healing. PLoS One 10 (3), e0120225. Jing, C., Jia-Han, W., Hong-Xing, Z., 2010. Double-edged effects of neuropeptide substance P on repair of cutaneous trauma. Wound Repair Regen 18 (3), 319–324. Jung, N., Yu, J., Um, J., Dubon, M.J., Park, K.S., 2016. Substance P modulates properties of normal and diabetic dermal fibroblasts. Tissue Eng. Regen. Med. 13 (2), 155–161. Kalden, D.H., Scholzen, T., Brzoska, T., Luger, T.A., 1999. Mechanisms of the antiinflammatory effects of alpha-MSH. Role of transcription factor NF-kappa B and adhesion molecule expression. Ann. N. Y. Acad. Sci. 885, 254–261. Kim, E.M., Grace, M.K., Welch, C.C., Billington, C.J., Levine, A.S., 1999. STZ-induced diabetes decreases and insulin normalizes POMC mRNA in arcuate nucleus and pituitary in rats. Am. J. Phys. 276 (5), R1320–R1326 Pt 2. Kitlinska, J., Lee, E.W., Movafagh, S., Pons, J., Zukowska, Z., 2002. Neuropeptide Yinduced angiogenesis in aging. Peptides 23 (1), 71–77. Koff, W.C., Dunegan, M.A., 1985. Modulation of macrophage-mediated tumoricidal
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G. Theocharidis and A. Veves
of calcitonin gene-related peptide in facilitation of wound healing and angiogenesis. Biomed. Pharmacother. 62 (6), 352–359. Tran, M.T., Ritchie, M.H., Lausch, R.N., Oakes, J.E., 2000. Calcitonin gene-related peptide induces IL-8 synthesis in human corneal epithelial cells. J. Immunol. 164 (8), 4307–4312. Um, J., Yu, J., Park, K.S., 2017. Substance P accelerates wound healing in type 2 diabetic mice through endothelial progenitor cell mobilization and Yes-associated protein activation. Mol. Med. Rep. 15 (5), 3035–3040. van Rossum, D., Hanisch, U.K., Quirion, R., 1997. Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors. Neurosci. Biobehav. Rev. 21 (5), 649–678. Vetrugno, R., Liguori, R., Cortelli, P., Montagna, P., 2003. Sympathetic skin response: basic mechanisms and clinical applications. Clin. Auton. Res. 13 (4), 256–270. Vishwanath, R., Mukherjee, R., 1996. Substance P promotes lymphocyte-endothelial cell adhesion preferentially via LFA-1/ICAM-1 interactions. J. Neuroimmunol. 71 (1–2), 163–171. Vockel, M., Pollok, S., Breitenbach, U., Ridderbusch, I., Kreienkamp, H.J., Brandner, J.M., 2011. Somatostatin inhibits cell migration and reduces cell counts of human keratinocytes and delays epidermal wound healing in an ex vivo wound model. PLoS One 6 (5), e19740. Wallengren, J., Badendick, K., Sundler, F., Hakanson, R., Zander, E., 1995. Innervation of the skin of the forearm in diabetic patients: relation to nerve function. Acta Derm. Venereol. 75 (1), 37–42. Wang, F., Millet, I., Bottomly, K., Vignery, A., 1992. Calcitonin gene-related peptide inhibits interleukin 2 production by murine T lymphocytes. J. Biol. Chem. 267 (29), 21052–21057. Weinstock, J.V., Blum, A., Walder, J., Walder, R., 1988. Eosinophils from granulomas in murine schistosomiasis mansoni produce substance P. J. Immunol. 141 (3), 961–966. Wheway, J., Herzog, H., Mackay, F., 2007. NPY and receptors in immune and inflammatory diseases. Curr. Top. Med. Chem. 7 (17), 1743–1752. Wimalawansa, S.J., 1997. Amylin, calcitonin gene-related peptide, calcitonin, and adrenomedullin: a peptide superfamily. Crit. Rev. Neurobiol. 11 (2–3), 167–239. Yamaguchi, M., Kojima, T., Kanekawa, M., Aihara, N., Nogimura, A., Kasai, K., 2004. Neuropeptides stimulate production of interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha in human dental pulp cells. Inflamm. Res. 53 (5), 199–204. Yaraee, R., Ebtekar, M., Ahmadiani, A., Sabahi, F., 2003. Neuropeptides (SP and CGRP) augment pro-inflammatory cytokine production in HSV-infected macrophages. Int. Immunopharmacol. 3 (13–14), 1883–1887. Yorek, M.A., Coppey, L.J., Gellett, J.S., Davidson, E.P., 2004. Sensory nerve innervation of epineurial arterioles of the sciatic nerve containing calcitonin gene-related peptide: effect of streptozotocin-induced diabetes. Exp. Diabesity Res. 5 (3), 187–193. Younan, G., Ogawa, R., Ramirez, M., Helm, D., Dastouri, P., Orgill, D.P., 2010. Analysis of nerve and neuropeptide patterns in vacuum-assisted closure-treated diabetic murine wounds. Plast Reconstr Surg 126 (1), 87–96. Zhang, J.S., Tan, Y.R., Xiang, Y., Luo, Z.Q., Qin, X.Q., 2006. Regulatory peptides modulate adhesion of polymorphonuclear leukocytes to bronchial epithelial cells through regulation of interleukins, ICAM-1 and NF-kappaB/IkappaB. Acta Biochim. Biophys. Sin. Shanghai 38 (2), 119–128. Zheng, Z., Liu, Y., Huang, W., Mo, Y., Lan, Y., Guo, R., et al., 2018. Neurotensin-loaded PLGA/CNC composite nanofiber membranes accelerate diabetic wound healing. Artif. Cells Nanomed. Biotechnol. 1–9. Zhu, F.B., Fang, X.J., Liu, D.W., Shao, Y., Zhang, H.Y., Peng, Y., et al., 2016. Substance P combined with epidermal stem cells promotes wound healing and nerve regeneration in diabetes mellitus. Neural Regen. Res. 11 (3), 493–501. Zukowska, Z., Pons, J., Lee, E.W., Li, L., 2003a. Neuropeptide Y: a new mediator linking sympathetic nerves, blood vessels and immune system? Can. J. Physiol. Pharmacol. 81 (2), 89–94. Zukowska, Z., Grant, D.S., Lee, E.W., 2003b. Neuropeptide Y: a novel mechanism for ischemic angiogenesis. Trends Cardiovasc. Med. 13 (2), 86–92.
interleukin-10 expression by human keratinocytes. Arch. Dermatol. Res. 290 (8), 425–428. Rodriguez-Pascual, F., Busnadiego, O., Gonzalez-Santamaria, J., 2014. The profibrotic role of endothelin-1: is the door still open for the treatment of fibrotic diseases? Life Sci. 118 (2), 156–164. Roosterman, D., Goerge, T., Schneider, S.W., Bunnett, N.W., Steinhoff, M., 2006. Neuronal control of skin function: the skin as a neuroimmunoendocrine organ. Physiol. Rev. 86 (4), 1309–1379. Russwurm, S., Stonans, I., Stonane, E., Wiederhold, M., Luber, A., Zipfel, P.F., et al., 2001. Procalcitonin and CGRP-1 mrna expression in various human tissues. Shock 16 (2), 109–112. Salo, P., Bray, R., Seerattan, R., Reno, C., McDougall, J., Hart, D.A., 2007. Neuropeptides regulate expression of matrix molecule, growth factor and inflammatory mediator mRNA in explants of normal and healing medial collateral ligament. Regul. Pept. 142 (1–2), 1–6. Salo, P.T., Beye, J.A., Seerattan, R.A., Leonard, C.A., Ivie, T.J., Bray, R.C., 2008. Plasticity of peptidergic innervation in healing rabbit medial collateral ligament. Can. J. Surg. 51 (3), 167–172. Schlereth, T., Schukraft, J., Kramer-Best, H.H., Geber, C., Ackermann, T., Birklein, F., 2016. Interaction of calcitonin gene related peptide (CGRP) and substance P (SP) in human skin. Neuropeptides 59, 57–62. Schratzberger, P., Reinisch, N., Prodinger, W.M., Kahler, C.M., Sitte, B.A., Bellmann, R., et al., 1997. Differential chemotactic activities of sensory neuropeptides for human peripheral blood mononuclear cells. J. Immunol. 158 (8), 3895–3901. Scott, J.R., Tamura, R.N., Muangman, P., Isik, F.F., Xie, C., Gibran, N.S., 2008. Topical substance P increases inflammatory cell density in genetically diabetic murine wounds. Wound Repair Regen. 16 (4), 529–533. Seidah, N.G., Benjannet, S., Hamelin, J., Mamarbachi, A.M., Basak, A., Marcinkiewicz, J., et al., 1999. The subtilisin/kexin family of precursor convertases. Emphasis on PC1, PC2/7B2, POMC and the novel enzyme SKI-1. Ann. N. Y. Acad. Sci. 885, 57–74. Service, F.J., Jay, J.M., Rizza, R.A., O’Brien, P.C., Go, V.L., 1986. Neurotensin in diabetes and obesity. Regul. Pept. 14 (1), 85–92. Sheppard, M.C., Bailey, C.J., Flatt, P.R., Swanston-Flatt, S.K., Shennan, K.I., 1985. Immunoreactive neurotensin in spontaneous syndromes of obesity and diabetes in mice. Acta Endocrinol. 108 (4), 532–536. Sheykhzade, M., Dalsgaard, G.T., Johansen, T., Nyborg, N.C., 2000. The effect of longterm streptozotocin-induced diabetes on contractile and relaxation responses of coronary arteries: selective attenuation of CGRP-induced relaxations. Br. J. Pharmacol. 129 (6), 1212–1218. Slominski, A., Wortsman, J., Mazurkiewicz, J.E., Matsuoka, L., Dietrich, J., Lawrence, K., et al., 1993. Detection of proopiomelanocortin-derived antigens in normal and pathologic human skin. J. Lab. Clin. Med. 122 (6), 658–666. Song, J.X., Wang, L.H., Yao, L., Xu, C., Wei, Z.H., Zheng, L.R., 2009. Impaired transient receptor potential vanilloid 1 in streptozotocin-induced diabetic hearts. Int. J. Cardiol. 134 (2), 290–292. Spenny, M.L., Muangman, P., Sullivan, S.R., Bunnett, N.W., Ansel, J.C., Olerud, J.E., et al., 2002. Neutral endopeptidase inhibition in diabetic wound repair. Wound Repair Regen. 10 (5), 295–301. Star, R.A., Rajora, N., Huang, J., Stock, R.C., Catania, A., Lipton, J.M., 1995. Evidence of autocrine modulation of macrophage nitric oxide synthase by alpha-melanocyte-stimulating hormone. Proc. Natl. Acad. Sci. U. S. A. 92 (17), 8016–8020. Strand, F.L., 1999. Neuropeptides: Regulators of Physiological Processes. MIT Press, Cambridge, Mass. Taherzadeh, S., Sharma, S., Chhajlani, V., Gantz, I., Rajora, N., Demitri, M.T., et al., 1999. Alpha-MSH and its receptors in regulation of tumor necrosis factor-alpha production by human monocyte/macrophages. Am. J. Phys. 276 (5), R1289–R1294 Pt 2. Thody, A.J., Ridley, K., Penny, R.J., Chalmers, R., Fisher, C., Shuster, S., 1983. MSH peptides are present in mammalian skin. Peptides 4 (6), 813–816. Toda, M., Suzuki, T., Hosono, K., Kurihara, Y., Kurihara, H., Hayashi, I., et al., 2008. Roles
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