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Chemokines in human obesity
Cytokine 127 (2020) 154953
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Chemokines in human obesity a
a
b
Volatiana Rakotoarivelo , Bhavesh Variya , Marie-France Langlois , Sheela Ramanathan a b
a,⁎
T
Department of Immunology and Cell Biology, CRCHUS, Sherbrooke, QC, Canada Division of Endocrinology, Department of Medicine, Université de Sherbrooke, CRCHUS, Sherbrooke, QC, Canada
A R T I C LE I N FO
A B S T R A C T
Keywords: Chemokines Human obesity Visceral adipose tissues Subcutaneous adipose tissues
Obesity and type 2 diabetes have been shown to be associated with chronic inflammation. Despite extensive evidence for inflammatory mediators in the obese patients and multiple clinical trials, the outcome has been disappointing. In murine models recruitment of immune cells during inflammation has been shown to contribute to the chronic inflammation. Clearcut evidence for the differential expression of chemokines that mediate this recruitment is not available. In this short review we discuss the observations on CCL2 and CCL5 in human obesity.
1. Introduction Chemokines or ‘chemotactic cytokines’ are small, secreted proteins that act as guides that regulate the navigation of leukocytes through lymphoid and non-lymphoid tissues. Chemokine gradient is maintained by the immobilization of chemokines on extracellular matrices through their interaction with glycosaminoglycans [1]. Chemokines signal through seven transmembrane-spanning G protein-coupled receptors that are phosphorylated and internalized resulting in transient desensitization to maintain directional cell migration [2]. In addition to mediating the migration of leukocytes, signals through chemokine receptors regulate cell survival, metastasis of tumor cells and are points of entry for certain viruses (Reviewed elsewhere [2]). The 50+ chemokines are named based on the positioning of the cysteine residues into CC, XC, CXC and CX3C ligands where the number following the X denotes the number of amino acids between the cysteine residues [2]. Each family of chemokines have their corresponding family of chemokine receptors that are classified as CCR, XCR, CXCR or CX3CR. While promiscuous interactions between the chemokines and their receptors are characteristics of this family of proteins, such interactions are restricted to the members within a given family. For example CCL5 can bind 4 different CCRs but will not interact with XCRs or CX3CRs. The interactions between chemokines and their receptors are further influenced by the presence of atypical chemokine receptors that lack intracellular signaling domains and chemokine mimics that can subvert immune responses. Chemokines are broadly classified into homeostatic, inflammatory or both based on their primary functions. Inflammatory chemokines such as CCL2 and CCL5 are produced during inflammation and help
recruit immune cells to sites of inflammation. These chemokines act on a wide variety of cells of the innate and adaptive immune system. On the other hand, homeostatic chemokines such as CXCL12 and CCL19 guide hematopoietic stem cells and certain leukocyte subsets during their development and migration from the bone marrow niche to the tissue of residence such as lymph nodes. Certain other chemokines are designated as dual-function chemokines as they regulate homeostatic migration of lymphocytes and their migration to inflamed tissues [3]. 2. Chemokines in obesity and metabolic syndrome Studies in animal models have suggested a role for inflammation as a causative factor in insulin resistance [4,5]. Adipose tissues are the primary sites of stockage of excess energy in the form of lipids. Tissue resident macrophages play an important role in maintaining their physiology. Recent studies have shown that macrophages resident in the adipose tissues are derived from the embryonic yolk sac, have the capacity for self-renewal and contribute to the homeostasis of the adipose tissues [6,7]. However, in obesity inflammatory monocytes can be recruited from circulation and contribute to the inflammatory process [8,9]. In light of the recent classification of macrophages, tissue-resident macrophages are not necessarily of ‘M2’ phenotype, but rather they are not inflammatory and they contribute to the maintenance of the tissue homeostasis. Recent studies suggest that in most tissues, following injury (or inflammation) resident and recruited macrophages can undergo conversion to an inflammatory phenotype. Following resolution of the injury, the remaining macrophages, irrespective of their origin, are imprinted with tissue specific functions [10]. Presence of inflammation-associated immune cells in obese adipose
⁎ Corresponding author at: Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001 North 12th Avenue, Sherbrooke QC J1H 5N4, Canada.
https://doi.org/10.1016/j.cyto.2019.154953 Received 22 May 2019; Received in revised form 7 December 2019; Accepted 7 December 2019 1043-4666/ © 2019 Elsevier Ltd. All rights reserved.
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fibroblasts and monocytes [15]. CCL2 primarily functions to recruit monocytes from circulation into inflamed tissues (Fig. 1). CCR2 expressed on immune cells appears to play an important, non-redundant role in the recruitment of monocytes and macrophages to the inflamed tissue [15]. Under homeostatic conditions most of the tissue-resident macrophages are seeded by precursors from yolk sac and/or fetal liver (Reviewed in [16]). However, the origin of tissue-resident macrophages in the adipose tissues is not known [16]. Even though CCL2 has been shown to contribute to both in situ proliferation and recruitment of monocytes from circulation [17,18], its absence had minimal effect on the infiltration of monocytes into the obese tissues in murine models of diet-induced obesity in 2 out of 3 studies [19–21]. Absence of CCL2 was accompanied by significantly reduced CCL7 levels, thereby ruling out the possibility that CCL7 might have compensated for the loss of CCL2 to recruit CCR2+ monocytes [19]. Analysis of macrophages and nonmacrophages in the stromal vascular fractions from CCL2 deficient mice revealed an increase in markers of inflammation in the latter suggesting that macrophages are not only source of inflammatory mediators in obese adipose tissues [19]. On the other hand CCR2 deficiency maintained insulin sensitivity even in high fat diet fed mice [22,23],
tissues naturally paved the way for the search for factors that contribute to their recruitment. Signaling through NF-κB plays an important role in the expression of chemokines [11]. Endoplasmic reticulum stress associated with increased generation of oxygen radicals and lipotoxicity activates Ikβ leading to the activation of NF-κB in adipose tissues [12]. Alternately, increased presence of inflammatory mediators in the adipose tissues can upregulate the expression of chemokines. However definitive evidence supporting a role for inflammation in promoting insulin resistance in humans is lacking [12–14]. Given the role of inflammation in obesity and insulin resistance, it is natural that various studies have analyzed the expression of chemokines in metabolic syndrome. In this review we will cover the implication of chemokines in animal models and correlate these observations with the status of chemokines in human obesity and metabolic syndrome. 3. CCR2-CCL2 axis CCL2 and CCL7 were initially characterized as the monocyte chemoattractant protein 1 and 3, respectively (MCP1 and MCP3) [2]. CCL2 is produced by different cell types such as endothelium, epithelium,
Fig. 1. Expression patterns of select chemokines in the visceral and subcutaneous adipose tissues. Expression pattern of the indicated chemokines in the visceral or subcutaneous adipose tissues from a given patient is indicated. Each color represents data for different chemokines in the indicated adipose tissue depot. The data has been adapted from [13]. 2
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4. CCL5/CCR5
probably as a consequence of the accumulation of eosinophils in the adipose tissues [24]. Despite the transient insulin resistance after 12 weeks of HFD, by 16 weeks, insulin sensitivity was ‘re-established’ [22,24]. The maintenance of insulin sensitivity in the CCR2 deficient mice at later time points was attributed to the increased infiltration by eosinophils in the adipose tissues that could have actively supported skewing towards M2-like macrophages as a consequence of increase in IL-5. Considered together, the results with CCL2 and CCR2 deficient mice suggest that insulin resistance is maintained independent of the de novo recruitment of monocytes to the adipose tissues. Further work is needed to understand the mechanism(s) by which targeting CCR2 might affect obesity and insulin resistance. In humans CCL2 is secreted by many cell types such as fibroblasts, monocytes and epithelial cells in most of the tissues [25–27]. The production of CCL2 by the pancreatic islets is not regulated by glucose. Similarly CCL2 does not directly affect insulin secretion [25], nevertheless lower levels of CCL2 production is associated with long-lasting insulin independence in autoimmune type 1 diabetes patients where the insulin producing beta cells are destroyed by the immune system. This observation suggests that islet-derived CCL2 can potentially recruit inflammatory immune cells. Adipocytes from obese individuals express significantly higher levels of mRNA for CCL2 [26]. However later studies reported an increase in CCL2 levels in subcutaneous adipose tissues that was not reflected in the serum [27,28]. Expression of inflammatory cytokines such as TNFα and IL-6 by adipose tissues correlates with the expression of CCL2 [13,29]. In fact, in our study [13] we observed that TNFα and IL-6, but not IFNγ showed strong correlation with CCL2 at the level of mRNA and protein in the visceral adipose tissues, strengthening the link between the expression of inflammatory cytokines and chemokines in adipose tissues. However, in this study expression of TNFA, IL6 and CCL2 did not correlate with the mRNA for CD68 in the visceral adipose tissue. Various studies have observed correlation between CD68 and TNFα, IL6 or CCL2 in the subcutaneous adipose tissues. The differences observed between the 2 adipose tissue depots could also be due to the fact that gene expression of CCL2 can vary by 6-fold in the visceral adipose tissues while the differences are modest in the subcutaneous adipose tissues [30,31]. Thus, the significance of the depot specific variations is not clear [13,32]. Atherosclerosis is another manifestation of metabolic syndrome resulting from the deposition of lipids in the form of plaques in arteries. The contribution of macrophages has been well characterized in this pathology in both humans and in mice. It is possible that CCL2 contributes in a significant manner in the progression of atherosclerosis where recruited monocytes play a significant role in the pathology. Plaque formation, but not circulating lipid concentration, is significantly reduced in Apoe-/- mice following anti-CCL2 gene therapy [33]. Unlike genetic deficiency, the treatment regimens targeting CCL2 will not result in complete neutralization, the later experiments would have contributed to dampening the inflammatory response without affecting all the functions of CCL2 in a temporal and contextual manner. Patients with cardiometabolic diseases show increased circulating levels of CCL2 [34]. In this study, visceral adiposity was determined by anthopometric parameters including visceral adiposity using CT scan in Korean patients with coronary artery disease. In parallel metabolic parameters and plasma CCL2 levels were determined. Despite the absence of central obesity, these patients had higher visceral adiposity and increased levels of circulating CCL2. Polymorphisms in CCL2 gene has been shown to be associated with carotid intimamedia thickness but its relevance to metabolic syndrome is not known [35]. Other studies have also shown a correlation between cardiovascular diseases and CCL2 [36,37]. Despite the implication of CCL2 in the recruitment of inflammatory monocytes to adipose tissues, inhibition of CCR2 did not affect the clinical outcome of type 2 diabetes in patients [38]. While it is possible that CCL2 can signal through CCR4, the physiological implication of this interaction in obesity is not clear.
CCL5 or RANTES is produced by different cell types such platelets, macrophages, eosinophils, fibroblasts and endothelium in addition to T cells where it was initially characterized. Its receptor CCR5 is a co-receptor for HIV infection [39]. CCL5 is a chemoattractant for T cells, NK cells, dendritic cells and eosinophils. The fact that CCL5 can compete for the receptor during HIV infections, had spurred the generation of biologics that target this interaction. In asthma, CCL5 produced by the epithelium lining the airways recruit eosinophils and exacerbates airway hyperresponsiveness in asthma. In addition to eosinophils, CCL5 can recruit neutrophils and monocytes. A naturally selected deletion variant of CCR5 (CCR5Δ32), the receptor for CCL5, does not come to the cell surface, thereby conferring resistance to HIV entry. As individuals carrying this mutation seem to survive without any obvious pathology, it is presumed that targeting this axis may not be deleterious [40]. Various studies analyzed the contribution of the absence of CCR5 signaling in atherosclerosis. Curiously, absence of CCR5 signaling due to CCR5Δ32 did not show any robust correlation except in Asian cohorts [41]. Incidence of atherosclerosis in individuals with mutant CCR5Δ32 had minimal effect or was higher based on the population studied [42–44]. Thus a beneficial role for targeting CCR5 axis is not supported by population studies. Several studies have shown that CCL5 is released by different fat deposits, although this distribution may be different from one tissue to another. The release of CCL5 by the abdominal adipose tissue is greater than by the subcutaneous tissues. [29,45]. While fatty and lean adipose tissues from obese individuals can constitutively produce detectable and significant amount of CCL5, its secretion is greater in adipose tissue from obese individuals [46]. Both immune cells that populate adipose tissue and the adipocytes themselves can be a source of this CCL5 [29]. The production of CCL5 by the non-immune cells may be in response to the stress, including the hypoxic conditions that is often seen in obese adipose tissue cells [46]. Adipose tissue derived CCL5 is one of the factors that can recruit immune cells, including macrophages, to adipose tissue. Indeed, the increase in the serum concentration of CCL5 is associated with type 2 diabetes [47]. Physical exercise was shown to reduce CCL5 levels in the adipose tissues [48]. However, other studies have not observed any definitive increase in CCL5 levels in obese patients [13]. Thus, the contribution of CCL5 to the inflammatory process in obesity is not clear. Very few studies have made a simultaneous analysis of multiple proinflammatory mediators in the serum or adipose tissue depots from obese patients [13,49,50]. We carried out a multiplex analyses of various chemokines and cytokines in visceral and subcutaneous adipose tissues obtained from patients undergoing bariatric surgery [12,13], with the aim of integrating the observations made by different groups that are ethnically, geographically and temporally different. The absence of concordance between these studies rather reflects the fact that inflammation can be promoted by different mediators. Furthermore, in our study, we were surprised to find that upto 30% of the obese samples did not express any of the known inflammatory mediators [13]. In this study, we also analyzed the expression of 8–10 chemokines in the adipose tissue depots. The expression of CCL2 positively correlated with TNFA expression in the visceral adipose tissues and TNFA with CD68 expression suggesting that macrophages might have contributed to the expression of TNFA which in turn would have increased the expression of CCL2. Again, these correlations were not strong in the sub-culatneous adipose tissues, indicating the differential response by the different adipose tissue depots. When we globally analyzed the expression of 10 chemokines in the adipose tissues, we were surprised to find that certain chemokines such as CCL2 and CCL5 were expressed in higher amounts when compared to others such as IL-8 or CCL11 in all the groups. Thus the absence of a strong candidate inflammatory marker in human obesity, despite the abundance of litterature on pre-clinical models begs the question on the continued characterization of the 3
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various pre-clinical models. There is no doubt that these pre-clinical models have contributed to our knowledge on the mechanisms by which chronic inflammation compounds the problem of insulin resistance and obesity. However, successful therapeutic approaches may not be obtained by persuing these lines of research [12,14]. Recent study on population health care based approaches (DiRECT) suggests that diabetes free remission can be achieved by pragmatic appraoch including diet control with structured long-term weight control program can have beneficial effects in a significant proportion of the population [51].
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Author contributions VR, SR and MFL planned the study. VR and SR wrote the manuscript. BV contributed to the discussion. All authors reviewed and corrected the manuscript. Funding This work was supported by CMDO (FRQS funded Research Network on Cardiometabolism, Diabetes and Obesity), CRCHUS and CIHR (MOP86530) to SR and MFL. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. References [1] G.J. Graham, T.M. Handel, A.E.I. Proudfoot, Leukocyte adhesion: reconceptualizing chemokine presentation by glycosaminoglycans, Trends Immunol. (2019). [2] J.W. Griffith, C.L. Sokol, A.D. Luster, Chemokines and chemokine receptors: positioning cells for host defense and immunity, Annu. Rev. Immunol. 32 (2014) 659–702. [3] B. Moser, M. Wolf, A. Walz, P. Loetscher, Chemokines: multiple levels of leukocyte migration control, Trends Immunol. 25 (2) (2004) 75–84. [4] J.M. Olefsky, C.K. Glass, Macrophages, inflammation, and insulin resistance, Annu. Rev. Physiol. 72 (2010) 219–246. [5] B.C. Lee, J. Lee, Cellular and molecular players in adipose tissue inflammation in the development of obesity-induced insulin resistance, Biochim. Biophys. Acta 1842 (3) (2014) 446–462. [6] C. Schulz, E. GomezPerdiguero, L. Chorro, H. Szabo-Rogers, N. Cagnard, K. Kierdorf, M. Prinz, B. Wu, S.E. Jacobsen, J.W. Pollard, J. Frampton, K.J. Liu, F. Geissmann, A lineage of myeloid cells independent of Myb and hematopoietic stem cells, Science (New York, N.Y) 336 (6077) (2012) 86–90. [7] S.F.H. Waqas, A.C. Hoang, Y.T. Lin, G. Ampem, H. Azegrouz, L. Balogh, J. Thuroczy, J.C. Chen, I.C. Gerling, S. Nam, J.S. Lim, J. Martinez-Ibanez, J.T. Real, S. Paschke, R. Quillet, S. Ayachi, F. Simonin, E.M. Schneider, J.A. Brinkman, D.W. Lamming, C.M. Seroogy, T. Roszer, Neuropeptide FF increases M2 activation and self-renewal of adipose tissue macrophages, J. Clin. Invest. 127 (9) (2017) 3559. [8] P.R. Nagareddy, M. Kraakman, S.L. Masters, R.A. Stirzaker, D.J. Gorman, R.W. Grant, D. Dragoljevic, E.S. Hong, A. Abdel-Latif, S.S. Smyth, S.H. Choi, J. Korner, K.E. Bornfeldt, E.A. Fisher, V.D. Dixit, A.R. Tall, I.J. Goldberg, A.J. Murphy, Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity, Cell Metab. 19 (5) (2014) 821–835. [9] L. Russo, C.N. Lumeng, Properties and functions of adipose tissue macrophages in obesity, Immunology 155 (4) (2018) 407–417. [10] D.A. Hume, K.M. Irvine, C. Pridans, The mononuclear phagocyte system: the relationship between monocytes and macrophages, Trends Immunol. 40 (2) (2019) 98–112. [11] F. Tourniaire, B. Romier-Crouzet, J.H. Lee, J. Marcotorchino, E. Gouranton, J. Salles, C. Malezet, J. Astier, P. Darmon, E. Blouin, S. Walrand, J. Ye, J.F. Landrier, Chemokine expression in inflamed adipose tissue is mainly mediated by NF-kappaB, PLoS ONE 8 (6) (2013) e66515. [12] V. Rakotoarivelo, B. Variya, S. Ilangumaran, M.F. Langlois, S. Ramanathan, Inflammation in human adipose tissues-Shades of gray, rather than white and brown, Cytokine Growth Factor Rev. 44 (2018) 28–37. [13] V. Rakotoarivelo, G. Lacraz, M. Mayhue, C. Brown, D. Rottembourg, J. Fradette, S. Ilangumaran, A. Menendez, M.F. Langlois, S. Ramanathan, Inflammatory cytokine profiles in visceral and subcutaneous adipose tissues of obese patients undergoing bariatric surgery reveal lack of correlation with obesity or diabetes, EBioMedicine 30 (2018) 237–247. [14] M.I. Maiorino, G. Bellastella, D. Giugliano, K. Esposito, Cooling down inflammation in type 2 diabetes: how strong is the evidence for cardiometabolic benefit?
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Contents lists available at ScienceDirect
Cytokine journal homepage: www.elsevier.com/locate/cytokine
Chemokines in human obesity a
a
b
Volatiana Rakotoarivelo , Bhavesh Variya , Marie-France Langlois , Sheela Ramanathan a b
a,⁎
T
Department of Immunology and Cell Biology, CRCHUS, Sherbrooke, QC, Canada Division of Endocrinology, Department of Medicine, Université de Sherbrooke, CRCHUS, Sherbrooke, QC, Canada
A R T I C LE I N FO
A B S T R A C T
Keywords: Chemokines Human obesity Visceral adipose tissues Subcutaneous adipose tissues
Obesity and type 2 diabetes have been shown to be associated with chronic inflammation. Despite extensive evidence for inflammatory mediators in the obese patients and multiple clinical trials, the outcome has been disappointing. In murine models recruitment of immune cells during inflammation has been shown to contribute to the chronic inflammation. Clearcut evidence for the differential expression of chemokines that mediate this recruitment is not available. In this short review we discuss the observations on CCL2 and CCL5 in human obesity.
1. Introduction Chemokines or ‘chemotactic cytokines’ are small, secreted proteins that act as guides that regulate the navigation of leukocytes through lymphoid and non-lymphoid tissues. Chemokine gradient is maintained by the immobilization of chemokines on extracellular matrices through their interaction with glycosaminoglycans [1]. Chemokines signal through seven transmembrane-spanning G protein-coupled receptors that are phosphorylated and internalized resulting in transient desensitization to maintain directional cell migration [2]. In addition to mediating the migration of leukocytes, signals through chemokine receptors regulate cell survival, metastasis of tumor cells and are points of entry for certain viruses (Reviewed elsewhere [2]). The 50+ chemokines are named based on the positioning of the cysteine residues into CC, XC, CXC and CX3C ligands where the number following the X denotes the number of amino acids between the cysteine residues [2]. Each family of chemokines have their corresponding family of chemokine receptors that are classified as CCR, XCR, CXCR or CX3CR. While promiscuous interactions between the chemokines and their receptors are characteristics of this family of proteins, such interactions are restricted to the members within a given family. For example CCL5 can bind 4 different CCRs but will not interact with XCRs or CX3CRs. The interactions between chemokines and their receptors are further influenced by the presence of atypical chemokine receptors that lack intracellular signaling domains and chemokine mimics that can subvert immune responses. Chemokines are broadly classified into homeostatic, inflammatory or both based on their primary functions. Inflammatory chemokines such as CCL2 and CCL5 are produced during inflammation and help
recruit immune cells to sites of inflammation. These chemokines act on a wide variety of cells of the innate and adaptive immune system. On the other hand, homeostatic chemokines such as CXCL12 and CCL19 guide hematopoietic stem cells and certain leukocyte subsets during their development and migration from the bone marrow niche to the tissue of residence such as lymph nodes. Certain other chemokines are designated as dual-function chemokines as they regulate homeostatic migration of lymphocytes and their migration to inflamed tissues [3]. 2. Chemokines in obesity and metabolic syndrome Studies in animal models have suggested a role for inflammation as a causative factor in insulin resistance [4,5]. Adipose tissues are the primary sites of stockage of excess energy in the form of lipids. Tissue resident macrophages play an important role in maintaining their physiology. Recent studies have shown that macrophages resident in the adipose tissues are derived from the embryonic yolk sac, have the capacity for self-renewal and contribute to the homeostasis of the adipose tissues [6,7]. However, in obesity inflammatory monocytes can be recruited from circulation and contribute to the inflammatory process [8,9]. In light of the recent classification of macrophages, tissue-resident macrophages are not necessarily of ‘M2’ phenotype, but rather they are not inflammatory and they contribute to the maintenance of the tissue homeostasis. Recent studies suggest that in most tissues, following injury (or inflammation) resident and recruited macrophages can undergo conversion to an inflammatory phenotype. Following resolution of the injury, the remaining macrophages, irrespective of their origin, are imprinted with tissue specific functions [10]. Presence of inflammation-associated immune cells in obese adipose
⁎ Corresponding author at: Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001 North 12th Avenue, Sherbrooke QC J1H 5N4, Canada.
https://doi.org/10.1016/j.cyto.2019.154953 Received 22 May 2019; Received in revised form 7 December 2019; Accepted 7 December 2019 1043-4666/ © 2019 Elsevier Ltd. All rights reserved.
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fibroblasts and monocytes [15]. CCL2 primarily functions to recruit monocytes from circulation into inflamed tissues (Fig. 1). CCR2 expressed on immune cells appears to play an important, non-redundant role in the recruitment of monocytes and macrophages to the inflamed tissue [15]. Under homeostatic conditions most of the tissue-resident macrophages are seeded by precursors from yolk sac and/or fetal liver (Reviewed in [16]). However, the origin of tissue-resident macrophages in the adipose tissues is not known [16]. Even though CCL2 has been shown to contribute to both in situ proliferation and recruitment of monocytes from circulation [17,18], its absence had minimal effect on the infiltration of monocytes into the obese tissues in murine models of diet-induced obesity in 2 out of 3 studies [19–21]. Absence of CCL2 was accompanied by significantly reduced CCL7 levels, thereby ruling out the possibility that CCL7 might have compensated for the loss of CCL2 to recruit CCR2+ monocytes [19]. Analysis of macrophages and nonmacrophages in the stromal vascular fractions from CCL2 deficient mice revealed an increase in markers of inflammation in the latter suggesting that macrophages are not only source of inflammatory mediators in obese adipose tissues [19]. On the other hand CCR2 deficiency maintained insulin sensitivity even in high fat diet fed mice [22,23],
tissues naturally paved the way for the search for factors that contribute to their recruitment. Signaling through NF-κB plays an important role in the expression of chemokines [11]. Endoplasmic reticulum stress associated with increased generation of oxygen radicals and lipotoxicity activates Ikβ leading to the activation of NF-κB in adipose tissues [12]. Alternately, increased presence of inflammatory mediators in the adipose tissues can upregulate the expression of chemokines. However definitive evidence supporting a role for inflammation in promoting insulin resistance in humans is lacking [12–14]. Given the role of inflammation in obesity and insulin resistance, it is natural that various studies have analyzed the expression of chemokines in metabolic syndrome. In this review we will cover the implication of chemokines in animal models and correlate these observations with the status of chemokines in human obesity and metabolic syndrome. 3. CCR2-CCL2 axis CCL2 and CCL7 were initially characterized as the monocyte chemoattractant protein 1 and 3, respectively (MCP1 and MCP3) [2]. CCL2 is produced by different cell types such as endothelium, epithelium,
Fig. 1. Expression patterns of select chemokines in the visceral and subcutaneous adipose tissues. Expression pattern of the indicated chemokines in the visceral or subcutaneous adipose tissues from a given patient is indicated. Each color represents data for different chemokines in the indicated adipose tissue depot. The data has been adapted from [13]. 2
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4. CCL5/CCR5
probably as a consequence of the accumulation of eosinophils in the adipose tissues [24]. Despite the transient insulin resistance after 12 weeks of HFD, by 16 weeks, insulin sensitivity was ‘re-established’ [22,24]. The maintenance of insulin sensitivity in the CCR2 deficient mice at later time points was attributed to the increased infiltration by eosinophils in the adipose tissues that could have actively supported skewing towards M2-like macrophages as a consequence of increase in IL-5. Considered together, the results with CCL2 and CCR2 deficient mice suggest that insulin resistance is maintained independent of the de novo recruitment of monocytes to the adipose tissues. Further work is needed to understand the mechanism(s) by which targeting CCR2 might affect obesity and insulin resistance. In humans CCL2 is secreted by many cell types such as fibroblasts, monocytes and epithelial cells in most of the tissues [25–27]. The production of CCL2 by the pancreatic islets is not regulated by glucose. Similarly CCL2 does not directly affect insulin secretion [25], nevertheless lower levels of CCL2 production is associated with long-lasting insulin independence in autoimmune type 1 diabetes patients where the insulin producing beta cells are destroyed by the immune system. This observation suggests that islet-derived CCL2 can potentially recruit inflammatory immune cells. Adipocytes from obese individuals express significantly higher levels of mRNA for CCL2 [26]. However later studies reported an increase in CCL2 levels in subcutaneous adipose tissues that was not reflected in the serum [27,28]. Expression of inflammatory cytokines such as TNFα and IL-6 by adipose tissues correlates with the expression of CCL2 [13,29]. In fact, in our study [13] we observed that TNFα and IL-6, but not IFNγ showed strong correlation with CCL2 at the level of mRNA and protein in the visceral adipose tissues, strengthening the link between the expression of inflammatory cytokines and chemokines in adipose tissues. However, in this study expression of TNFA, IL6 and CCL2 did not correlate with the mRNA for CD68 in the visceral adipose tissue. Various studies have observed correlation between CD68 and TNFα, IL6 or CCL2 in the subcutaneous adipose tissues. The differences observed between the 2 adipose tissue depots could also be due to the fact that gene expression of CCL2 can vary by 6-fold in the visceral adipose tissues while the differences are modest in the subcutaneous adipose tissues [30,31]. Thus, the significance of the depot specific variations is not clear [13,32]. Atherosclerosis is another manifestation of metabolic syndrome resulting from the deposition of lipids in the form of plaques in arteries. The contribution of macrophages has been well characterized in this pathology in both humans and in mice. It is possible that CCL2 contributes in a significant manner in the progression of atherosclerosis where recruited monocytes play a significant role in the pathology. Plaque formation, but not circulating lipid concentration, is significantly reduced in Apoe-/- mice following anti-CCL2 gene therapy [33]. Unlike genetic deficiency, the treatment regimens targeting CCL2 will not result in complete neutralization, the later experiments would have contributed to dampening the inflammatory response without affecting all the functions of CCL2 in a temporal and contextual manner. Patients with cardiometabolic diseases show increased circulating levels of CCL2 [34]. In this study, visceral adiposity was determined by anthopometric parameters including visceral adiposity using CT scan in Korean patients with coronary artery disease. In parallel metabolic parameters and plasma CCL2 levels were determined. Despite the absence of central obesity, these patients had higher visceral adiposity and increased levels of circulating CCL2. Polymorphisms in CCL2 gene has been shown to be associated with carotid intimamedia thickness but its relevance to metabolic syndrome is not known [35]. Other studies have also shown a correlation between cardiovascular diseases and CCL2 [36,37]. Despite the implication of CCL2 in the recruitment of inflammatory monocytes to adipose tissues, inhibition of CCR2 did not affect the clinical outcome of type 2 diabetes in patients [38]. While it is possible that CCL2 can signal through CCR4, the physiological implication of this interaction in obesity is not clear.
CCL5 or RANTES is produced by different cell types such platelets, macrophages, eosinophils, fibroblasts and endothelium in addition to T cells where it was initially characterized. Its receptor CCR5 is a co-receptor for HIV infection [39]. CCL5 is a chemoattractant for T cells, NK cells, dendritic cells and eosinophils. The fact that CCL5 can compete for the receptor during HIV infections, had spurred the generation of biologics that target this interaction. In asthma, CCL5 produced by the epithelium lining the airways recruit eosinophils and exacerbates airway hyperresponsiveness in asthma. In addition to eosinophils, CCL5 can recruit neutrophils and monocytes. A naturally selected deletion variant of CCR5 (CCR5Δ32), the receptor for CCL5, does not come to the cell surface, thereby conferring resistance to HIV entry. As individuals carrying this mutation seem to survive without any obvious pathology, it is presumed that targeting this axis may not be deleterious [40]. Various studies analyzed the contribution of the absence of CCR5 signaling in atherosclerosis. Curiously, absence of CCR5 signaling due to CCR5Δ32 did not show any robust correlation except in Asian cohorts [41]. Incidence of atherosclerosis in individuals with mutant CCR5Δ32 had minimal effect or was higher based on the population studied [42–44]. Thus a beneficial role for targeting CCR5 axis is not supported by population studies. Several studies have shown that CCL5 is released by different fat deposits, although this distribution may be different from one tissue to another. The release of CCL5 by the abdominal adipose tissue is greater than by the subcutaneous tissues. [29,45]. While fatty and lean adipose tissues from obese individuals can constitutively produce detectable and significant amount of CCL5, its secretion is greater in adipose tissue from obese individuals [46]. Both immune cells that populate adipose tissue and the adipocytes themselves can be a source of this CCL5 [29]. The production of CCL5 by the non-immune cells may be in response to the stress, including the hypoxic conditions that is often seen in obese adipose tissue cells [46]. Adipose tissue derived CCL5 is one of the factors that can recruit immune cells, including macrophages, to adipose tissue. Indeed, the increase in the serum concentration of CCL5 is associated with type 2 diabetes [47]. Physical exercise was shown to reduce CCL5 levels in the adipose tissues [48]. However, other studies have not observed any definitive increase in CCL5 levels in obese patients [13]. Thus, the contribution of CCL5 to the inflammatory process in obesity is not clear. Very few studies have made a simultaneous analysis of multiple proinflammatory mediators in the serum or adipose tissue depots from obese patients [13,49,50]. We carried out a multiplex analyses of various chemokines and cytokines in visceral and subcutaneous adipose tissues obtained from patients undergoing bariatric surgery [12,13], with the aim of integrating the observations made by different groups that are ethnically, geographically and temporally different. The absence of concordance between these studies rather reflects the fact that inflammation can be promoted by different mediators. Furthermore, in our study, we were surprised to find that upto 30% of the obese samples did not express any of the known inflammatory mediators [13]. In this study, we also analyzed the expression of 8–10 chemokines in the adipose tissue depots. The expression of CCL2 positively correlated with TNFA expression in the visceral adipose tissues and TNFA with CD68 expression suggesting that macrophages might have contributed to the expression of TNFA which in turn would have increased the expression of CCL2. Again, these correlations were not strong in the sub-culatneous adipose tissues, indicating the differential response by the different adipose tissue depots. When we globally analyzed the expression of 10 chemokines in the adipose tissues, we were surprised to find that certain chemokines such as CCL2 and CCL5 were expressed in higher amounts when compared to others such as IL-8 or CCL11 in all the groups. Thus the absence of a strong candidate inflammatory marker in human obesity, despite the abundance of litterature on pre-clinical models begs the question on the continued characterization of the 3
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various pre-clinical models. There is no doubt that these pre-clinical models have contributed to our knowledge on the mechanisms by which chronic inflammation compounds the problem of insulin resistance and obesity. However, successful therapeutic approaches may not be obtained by persuing these lines of research [12,14]. Recent study on population health care based approaches (DiRECT) suggests that diabetes free remission can be achieved by pragmatic appraoch including diet control with structured long-term weight control program can have beneficial effects in a significant proportion of the population [51].
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