Leptin in autoimmune diseases

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Available online at www.sciencedirect.com

Metabolism www.metabolismjournal.com

Review

Leptin in autoimmune diseases Claudio Procaccini a , Valentina Pucino b , Christos S. Mantzoros c, d, e , Giuseppe Matarese f, g,⁎ a

Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR) c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli “Federico II”, 80131 Napoli, Italy b Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di Napoli “Federico II”, 80131 Napoli, Italy c Section of Endocrinology, Boston VA Healthcare System, Jamaica Plain, MA d Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA e Department of Medicine, Boston Medical Center, Boston University, 72 Evans Street, Boston, MA 02217, USA f Dipartimento di Medicina e Chirurgia, Facoltà di Medicina e Chirurgia, Università di Salerno, Baronissi Campus, 84081 Baronissi, Salerno, Italy g IRCCS–MultiMedica, 20138 Milano, Italy

A R T I C LE I N FO

AB S T R A C T

Keywords:

The past twenty years of research on leptin has provided crucial information on the link

Leptin

between metabolic state and immune system function. Adipocytes influence not only the

Metabolism

endocrine system but also the immune response, through several cytokine-like mediators

T cells

known as adipokines, which include leptin. Initially described as an antiobesity hormone,

Autoimmunity

leptin has subsequently been shown also to influence hematopoiesis, thermogenesis, reproduction, angiogenesis, and more importantly immune homeostasis. As a cytokine, leptin can affect thymic homeostasis and the secretion of acute-phase reactants such as interleukin-1 (IL-1) and tumor-necrosis factor-alpha (TNF-α). Leptin links nutritional status and proinflammatory T helper 1 (Th1) immune responses and the decrease in leptin plasma concentration during food deprivation leads to impaired immune function. Conversely, elevated circulating leptin levels in obesity appear to contribute to the low-grade inflammatory background which makes obese individuals more susceptible to increased risk of developing cardiovascular diseases, diabetes, or degenerative disease including autoimmunity and cancer. In this review, we provide an overview of recent advances on the role of leptin in the pathogenesis of several autoimmune disorders that may be of particular relevance in the modulation of the autoimmune attack through metabolic-based therapeutic approaches. © 2014 Elsevier Inc. All rights reserved.

Abbreviations: LepRb, leptin receptor b; Th, T helper; Tconv cells, conventional T cells; Treg cells, regulatory T cells; mTOR, mammalian target of rapamycin; MS, multiple sclerosis; RRMS, relapsing-remitting multiple sclerosis; EAE, experimental autoimmune encephalomyelitis; IBD, inflammatory bowel disease; RA, rheumatoid arthritis; T1D, type 1 diabetes; SLE, systemic lupus erythematosus; Pso, psoriasis; AT, autoimmune thyroiditis; HT, Hashimoto thyroiditis; EIC, experimental induced colitis; BMI, body mass index; CNS, central nervous system; NPY, neuropeptide Y; NOS, nitic oxide synthase; NOD, Non-obese diabetic; ob/ob, leptin-deficient; db/db, leptin-receptordeficient; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; STAT, signal transducer and activator of transcription; SOCS-3, suppressor of cytokine signaling-3. ⁎ Corresponding author at: Dipartimento di Medicina e Chirurgia, Facoltà di Medicina, Università di Salerno, Baronissi Campus, Baronissi, Salerno 84081, Italy. E-mail address: [email protected] (G. Matarese). http://dx.doi.org/10.1016/j.metabol.2014.10.014 0026-0495/© 2014 Elsevier Inc. All rights reserved.

Please cite this article as: Procaccini C, et al, Leptin in autoimmune diseases, Metabolism (2014), http://dx.doi.org/10.1016/j. metabol.2014.10.014

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Introduction

Leptin is one of the most important hormones secreted by adipose tissue [1] and its implication in energetic homeostasis at central level has been largely described [2]. The past twenty years of research on adipose tissue has provided important insights into the intricate network that links nutrition, metabolism and immune homeostasis. In this context leptin works not only as a “fasting hormone” by controlling body weight through the inhibition of food intake and stimulation of energy expenditure by increased thermogenesis [3] but also in the regulation of peripheral functions [4–9]. Indeed, it has been previously shown that ob/ob and db/db mice are not only obese but also show many other immune/endocrine alterations observed during starvation [10–12]. Although an important role of leptin is to regulate body weight through the inhibition of food intake, recent evidence has indicated that leptin is also involved in the modulation of several innate and adaptive immune responses [13]. Indeed, LepR is expressed by several immune cells, thus suggesting a key role displayed by leptin in the regulation of immune responses [14]. Modulation of the immune system by leptin is exerted at the development, proliferation, anti-apoptotic, maturation, and activation levels [15]. Indeed, LepRs have been found in neutrophils, monocytes, and lymphocytes, and they belong to the family of class I cytokine receptors. The overall leptin action in the immune system is a pro-inflammatory effect, activating pro-inflammatory cells, promoting Th1 responses, and mediating the production of the other pro-inflammatory cytokines, such as TNF-α, IL-2, or IL-6. Leptin is therefore able to modulate both innate and adaptive immune response [13]. Moreover, several studies in human revealed that leptin levels associated with autoimmune disorders, infections and endocrine/metabolic diseases, thus suggesting a central role of leptin in immune homeostasis and in the pathogenesis of several inflammatory disorders [16–18]. This review analyzes the role of leptin in immune homeostasis, and the direct and indirect influences of leptin on inflammation and autoimmunity.

of human circulating monocytes in vitro [31]. Moreover, leptin can induce chemotaxis of neutrophils and the release of oxygen radicals [32–34]. In NK cells, leptin is involved in all processes of cell development, differentiation, proliferation, activation, and cytotoxicity [35,36]. The effects of leptin on adaptive immune responses have been extensively investigated on human CD4+ T cells (Fig. 1) [37]. Addition of physiological concentrations of leptin to a mixed lymphocyte reaction induces a dose-dependent increase in CD4+ T cell proliferation [10]. Leptin induces early (CD69) and late activation markers (CD25, CD71) in both CD4+

Adipose Tissue

Higher Leptin

+

x

Tconv cells

Treg cells

TNF-α α, IL-1, IFN-γ

Increased risk and susceptibility to autoimmunity and chronic inflammation - Multiple sclerosis - Rheumatoid arthritis

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Role of leptin in immune response

Mice lacking leptin or its functional receptor have a number of defects in both cell-mediated and humoral immunity [19,20]. Similarly, humans with congenital leptin deficiency have a much higher incidence of infection-related death during childhood [21], whereas recombinant human leptin administration in two children with congenital leptin deficiency and in females with acquired hypoleptinemia [22,23] normalized absolute numbers of naive CD4+CD45RA+ T cells and nearly restored the proliferation response and the cytokine release profile. A number of studies in mice have shown that the effect of leptin on the immune system is both direct and indirect, i.e., via modulation of central or peripheral pathways [12,24–26]. Leptin has a well-established role in innate immunity control. In macrophages/monocytes, leptin up-regulates phagocytic function [27] via phospholipase activation [28] as well as proinflammatory cytokine secretion, such as TNF-α, IL-6, and IL-12 [29,30]. Leptin stimulates the proliferation and activation

- Systemic lupus erythematosus - Type 1 diabetes - Inflammatory bowel diseases - Autoimmune thyroiditis - Psoriasis

Fig. 1 – Schematic model of leptin role in pathogenesis of autoimmunity. The high amount of leptin secreted by adipocytes in inflammatory conditions, such as overweight, is associated with an high frequency and expansion of peripheral and in situ conventional CD4+ T cells (Tconv), secreting high amount of pro-inflammatory cytokines (IFNγ, TNF-α, IL-1) and a low proportion of regulatory T cells (Treg); this imbalance could generate an altered control of metabolic functions, an increased incidence of autoimmune disorders and chronic inflammation.

Please cite this article as: Procaccini C, et al, Leptin in autoimmune diseases, Metabolism (2014), http://dx.doi.org/10.1016/j. metabol.2014.10.014

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and CD8+ lymphocytes [38]. However, leptin has different effects on proliferation and cytokine production by human naive (CD45RA) and memory (CD45RO) CD4+ T cells. Leptin promotes the proliferation and IL-2 secretion by naive T cells and, on memory T cells, promotes the switch toward Th1-cell immune responses by increasing IFN-γ and TNF-α secretion, IgG2a production from B cells, and by promoting delayed-type hypersensitivity (DTH) responses [10]. Recent evidence indicates that leptin also affects the generation, maturation and survival of thymic T cells by decreasing their rate of apoptosis [39]. Indeed, acute caloric deprivation causes a rapid decrease of serum leptin concentration accompanied by reduced DTH responses and thymic atrophy, which are reversible with administration of leptin [39]. Recently, it has been reported that leptin can act as a negative signal for the expansion of human naturally occurring Foxp3+CD4+CD25high Treg cells [40] (Fig. 1), a cellular subset which suppresses autoreactive response mediated by CD4+25− Tconv cells. De Rosa et al. showed that freshly isolated Treg cells produce leptin and express high levels of LepR. In vitro leptin neutralization resulted in Treg cells proliferation [40]. Very recently a paper by the same group has shown that leptin activates the mTOR pathway to control Treg cells responsiveness [41] and Tconv cells functions [42,43]. More specifically leptin inhibited rapamycin-induced proliferation of Tregs, by increasing activation of the mTOR pathway. In addition, under normal conditions, Tregs secreted leptin, which activated mTOR in an autocrine manner to maintain their state of hyporesponsiveness. Finally, Tregs from db/db mice exhibited a decreased mTOR activity and increased proliferation compared with that of wild-type cells [41]. Interestingly, leptin has been demonstrated to exert opposite effects on Tconv cells, where it enhances their proliferation through the activation of mTOR pathway [42]. Finally it has been also shown that leptin facilitates Th17 responses by inducing RORγt transcription in CD4+ T cells [44] in (NZB/NZW)F1 lupus-prone mice, whereas on the contrary its neutralization inhibits Th17 responses [44].

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Leptin and multiple sclerosis

MS is the most common chronic inflammatory demyelinating disease of the CNS, characterized by localized areas of inflammation, demyelination, axonal loss and gliosis in the brain and spinal cord, resulting in a variety of neurological symptoms. MS mainly affects young people with onset usually at the age of 20–50 and the prevalence is increasing in recent decades [45]. The cause of MS has not been fully elucidated, however, genetic, environmental and immunological factors have been implicated in the etiology of the disease [46,47]. In the last few years, several studies investigated obesity during childhood and late adolescence as a risk factor of developing MS [48–52]. Indeed, two large studies, one in American women [48] and the other based on a Swedish population [49], demonstrated a twofold increased risk of developing MS among subjects with a BMI ≥30 kg/m2 at age 18 and 20 respectively, compared with normal weight subjects. Also Munger et al. [50] found that a higher BMI at ages 7–13 was associated with a significant increased risk of MS only among girls. In this context, the immunomodulatory effects

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of leptin have been linked to enhanced susceptibility to EAE, a mouse model of multiple sclerosis [18]. Leptin has been shown to be involved in the induction and progression of EAE [18,53,54]. The ob/ob mice are resistant to EAE induction, a condition associated with increased IL-4 and a lack of IFN-γ secretion after myelin-specific stimulation of T cells. Interestingly, leptin replacement renders these mice susceptible to the disease, secondary to a shift toward a Th1-type cytokine pattern and to the reversal of IgG1 to the Th1-dependent IgG2a [18], whereas administration of leptin to susceptible wild-type mice worsens EAE by increasing the secretion of pro-inflammatory cytokines and directly correlates with pathogenic T-cell autoreactivity [53,54]. Notably, leptin is expressed by T cells and macrophages in both the lymph nodes and active inflammatory lesions of the CNS during acute and relapsing EAE, but not during remission [54]. The role of leptin in EAE has further established with leptin neutralization experiments in WT mice. This kind of treatment significantly improved clinical score and delayed disease progression, by inhibiting T cell autoreactivity during EAE progression [55]. Moreover recent evidence has shown that the adipose tissue, through leptin, has a key role in the survival of autoreactive CD4+ T cells in vivo. Galgani et al. have found that leptin regulates the survival of autoantigenspecific CD4+ T cells directly through the activation of mTOR and the survival gene Bcl-2, and indirectly through a reduced secretion of cytokines important for autoreactive CD4+ T cell survival [56]. In addition, Ouyand et al. have recently shown that leukocyte infiltration into spinal cord of EAE-affected mice is attenuated by removal of endothelial leptin signaling, thus suggesting that leptin signaling might exacerbate blood– brain barrier dysfunction to worsen EAE [57]. In human studies, the expression of LepR has been found to be significantly higher in CD8+ T cells and monocytes from MS patients in relapse phase than those observed in patients in remission (or in healthy controls). Moreover relapsing patients display high levels of P-STAT-3 and low expression of SOCS-3 and exogenous leptin treatment sustains STAT-3 phosphorylation only in the monocytes from relapsing patients, suggesting that LepR might play a role in the modulation of clinical relapses during MS [58]. A recent gene microarray analysis of Th1 lymphocytes from active MS lesions has shown elevated transcripts of many genes of the neuroimmunoendocrine axis, including leptin [59]. Confirming these data, increased leptin expression has recently been described in active inflammatory lesions of the CNS in patients with MS [59] and in the sera of patients with MS before relapses after treatment with IFN-β [60]. Also Matarese et al. demonstrated that leptin production was significantly increased in both serum and CSF (cerebrospinal fluid) of RRMS patients, an aspect that positively correlates with the secretion of IFN-γ in the CSF and inversely correlates with the percentage of circulating Treg cells [61]. As common obesity is generally characterized by elevated serum leptin associated with central hypothalamic resistance to leptin, it is conceivable not only to study circulating Treg cells but also intra-adipose tissue-resident Treg cells. In this sense, recent reports have shown that normal adipose tissue is a site of preferential accumulation of Treg cells [62–64]. In line with this evidence, recent reports have shown that caloric restriction (CR), with consequent lowering of serum

Please cite this article as: Procaccini C, et al, Leptin in autoimmune diseases, Metabolism (2014), http://dx.doi.org/10.1016/j. metabol.2014.10.014

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leptin, can significantly increase the survival and lifespan in experimental animal models of inflammation, being beneficial also in MS [65]. In humans, Fontana and colleagues have shown that CR is able to significantly reduce inflammatory parameters [66], suggesting that the nutritional intervention is able to dampen inflammatory responses. CR ameliorates clinical EAE and reduces inflammation, demyelination, and axon injury — without suppressing immune functions [65], increasing plasma levels of corticosterone and adiponectin and decreasing plasma levels of leptin and IL-6. Other possibilities include CR-associated increase in ghrelin, NPY and endocannabinoids — all of which can dampen EAE and are increased during CR and starvation [67,68].

4.

Leptin and inflammatory bowel disease

IBD is characterized by anorexia, malnutrition, altered body composition, and development of mesenteric white adipose tissue (WAT) hypertrophy. Crohn's disease (CD) and ulcerative colitis (UC) are the main forms of IBD, a group of chronic, idiopathic, pathological conditions affecting the gut, characterized by a relapsing–remitting course and the frequent development of various intestinal and extra-intestinal complications. The precise cause of inflammatory bowel disease is unknown; however, genetically susceptible individuals seem to have a dysregulated mucosal immune response to commensal gut flora, which results in bowel inflammation [69–72]. Increasing evidence suggests that adipokines synthesized either in WAT or in immune cells are involved in these manifestations of IBD. The prevalence of IBD has dramatically increased mainly in Western countries in the past 50 years [73] and environmental factors are likely to have a preponderant role in this phenomenon. The correlation between obesity and an increased risk of CD has been recently found in a large study (OR = 1.02–3.47) [74]. Moreover, epidemiological evidence suggests that a high dietary intake of fat increases the risk of IBD development [75]. The role of leptin in the pathogenesis of IBD has been examined in several experimental rodent models of intestinal inflammation as well as in IBD patients. It has been shown that dextran sodium sulfate (DSS)-induced colitis in mice delayed the puberty in male mice out of proportion to changes in food intake, body weight and serum leptin level [76]. In rats, trinitrobenzene sulfonic acid (TNBS)-induced colitis results in increased leptin concentration and is associated with decreased food intake, anorexia and weight loss [77]. Interestingly ob/ob mice are resistant to acute and chronic intestinal inflammation induced by DSS and to colitis induced by TNBS [78] as they show decreased secretion of pro-inflammatory cytokines and chemokines, a condition reverted by leptin [78]. In addition CD4+CD45RBhigh T-cells from db/db mice do not induce colitis as rapidly as do CD4+CD45RBhigh T-cells from non db/db mice, when transferred to T-cell-deficient (scid) mice [79] and subcutaneous transplantation of WAT from WT littermates increased leptin and normalized metabolic, immune and inflammatory parameters of ob/ob mice [80]. Recently, Singh et al. have shown that tested pegylated leptin antagonist (PEG-MLA) effectively attenuated the overall clinical score of colitis by decreasing body weight, systemic

serum amyloid A (SAA), leptin levels, systemic and mucosal inflammatory cytokine expression, and by increasing insulin levels and enhanced systemic and mucosal Tregs in mice with chronic colitis [81]. Of interest, recent reports have shown that leptin secreted by the gastric mucosa is not completely degraded by proteolysis and can therefore reach the intestine in an active form, where it can control the expression of sodium/glucose and peptide transporters on intestinal epithelial cells [82,83], functioning as a growth factor for the intestine [82,83]. Contrasting results on the role of obesity and leptin in IBD were obtained in human studies. Two clinical studies have correlated a high BMI with an unfavorable course of IBD, including a higher risk of relapses, abscesses, surgical complications [84,85]. Of note, LepR is present in brush border, basolateral membrane, and cytoplasm of enterocytes [86]. Inflamed colonic epithelial cells from UC patients expressed and released leptin into the intestinal lumen. Leptin in turn, induced epithelial wall damage and neutrophil infiltration that represent characteristic histological findings in acute intestinal inflammation [87]. An overexpression of leptin mRNA in WAT was reported in IBD patients compared to controls, indicating that leptin might participate in the inflammatory process by enhancing mesenteric TNF-α expression [88]. In IBD patients, systemic leptin levels are increased compared to normal healthy donors [89–91] and, confirming these data, in a recent study, it has been shown that expression and release of leptin increases in UC patients with infectious diarrhea [92]. These results are in contradiction with some earlier studies on both human and experimental models, in which obesity has not been associated with inflammation, but which rather suggest that leptin levels correlate with percent of body fat, and percentage of leptin is increased during weight gain and decreased during weight loss [93–95]. Recently, Karmiris et al. have shown that serum leptin levels were decreased in IBD patients compared to healthy controls, irrespective of sex, age, CRP, years of diagnosis, and disease activity and localization. More specifically, patients with a BMI < 25 had lower serum leptin levels compared to patients with BMI ≥ 25 [90,91]. Finally, in a recent study, it was shown that children with IBD have significant under nutrition and lower leptin levels than controls [96]. The role of leptin in IBD has been studied, but the results are conflicting and more importantly clinical studies are lacking on this topic, therefore further investigations, that would likely clarify leptin involvement in the pathogenesis of IBD, are required.

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Leptin and rheumatoid arthritis

RA is a multifactorial inflammatory disease affecting joints and other organs. Chronic synovial inflammation in RA leads to progressive damage to articular cartilage and bone and could result in disability. Inflammatory cells in the synovium produce cytokines that activate proliferation of synovial fibroblasts and macrophages leading to bone erosions. However, it is recognized that RA synovitis is a heterogeneous pathology with diverse cellular and molecular phenotypes [97]. It has been shown that interactions between neuroendocrine and immune systems contribute to the

Please cite this article as: Procaccini C, et al, Leptin in autoimmune diseases, Metabolism (2014), http://dx.doi.org/10.1016/j. metabol.2014.10.014

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pathogenesis of rheumatic diseases such as RA [98,99]. In this context leptin plays a key role in the pathogenesis of RA. Indeed, it has recently been found that ob/ob mice could develop resistance to experimental antigen-induced arthritis compared to wild-type mice [100]. In addition, it has been reported that fasting, which is associated with a marked decrease in serum leptin concentration, determines a shift toward Th2-type cytokine secretion, thus improving clinical disease activity in RA patients by decreasing CD4 + activation [12]. Regarding leptin's direct activity on chondrocytes, it has been showed that leptin induced, in synergy with IFN-γ and IL-1, NOS type II activation in cultured chondrocytes [101]. These events induce a wide range of pro-inflammatory cytokines in joint cartilage, causing chondrocyte phenotype loss, apoptosis, metalloproteases activation and consequently inflammation [102,103]. However there is some controversial evidence on the role of leptin in the pathogenesis of RA [104]. Several studies have found significantly elevated serum levels of leptin in RA patients [105–108], while others have showed low levels of this adipocytokine [109]. It has been reported that serum leptin levels were higher in patients with erosive RA [110,111]. However, some other studies have reported that serum leptin levels of RA patients were not different from controls [112,113], and were correlated significantly with BMI but not with disease activity stage (DAS) [112,114,115]. Emerging studies of leptin in synovial fluid and synovial tissue in RA have also been reported. Seven et al. [116] found that serum and synovial fluid leptin levels were higher in RA patients when compared to the control group. Accordingly, this phenomenon also appeared in moderate disease activity (DAS > 2.7) patients compared to those with low disease activity (DAS < 2.7). Contrasting results by Bokarewa et al. [105] have shown a lower leptin level in synovial fluid than in serum of RA patients; the same group also found a positive correlation between the consumption of leptin in the synovial fluid and the absence of bone erosions thus suggesting that leptin consumption in the joints may be involved in protection against erosions, and therefore that leptin might be able to protect against bone erosion. In line with this evidence there are a growing number of studies which have shown that circulating leptin did not correlate with radiographics progressions in RA [117,118]. Gunaydin et al. found that, although leptin serum levels were higher in patients with RA, no correlation was observed between leptin levels and disease duration, number of painful and swollen joints, disease activity score 28 (DAS28), ESR, CRP and TNF-α, and use of corticoid and methotrexate [119]. On the contrary, Yoshino et al. found that leptin significantly correlated to CRP levels in RA patients, indicating that it may act as proinflammatory cytokine in RA. In another study, leptin levels have been correlated with markers of inflammation (IL-6, CRP) during anti-TNF-α treatment [106]; no difference in leptin concentration between patients with RA and controls, but an inverse correlation with inflammation has been found. Finally, reduction of leptin levels in RA patients, by fasting, has been found to ameliorate the clinical symptoms of several autoimmune disease including RA [13], thus suggesting that leptin antagonism could be proposed for the prevention of developing RA.

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Leptin and systemic lupus erythematosus

SLE is a systemic disease, affecting predominantly young women, which is characterized by chronic autoimmune responses against multiple nuclear self-antigens and by multisystem organ involvement, ranging from relatively mild manifestations (skin rash or non-erosive arthritis) to severe or life threatening complications (nephritis, neuropsychiatric disorders, cardiac involvement), and a wide profile of autoantibodies [120,121]. In SLE, an impaired clearance of cell-derived materials can result in the accumulation of immunogenic selfantigens that facilitate the development of autoimmune responses and subsequent inflammation [122] with abnormal circulating levels of multiple cytokines and hormones [123]. Adipokines are increased in SLE [124–126] but most studies did not report correlations with disease activity. Little is known on how leptin can contribute to the pathogenesis of SLE [127]. Several studies reported elevated levels of circulating leptin in SLE patients compared to healthy controls [128–130]. However, contrasting results showed no statistical association between leptin levels and disease activity as determined by the MexSLEDAI score [129,130]. Leptin has been suggested to have a role also in modulating the cardiovascular risk of SLE patients. Indeed it has been reported that leptin and high-fat diet are able to induce proinflammatory high-density lipoproteins and atherosclerosis in BWF1 lupus-prone mice, thus suggesting that environmental factors associated with obesity and metabolic syndrome can accelerate atherosclerosis and disease in a lupus-prone background [128]. However, there was no significant relationship between higher leptin levels and coronary calcification between SLE patients and controls. In another study a significant correlation between leptin, insulin levels, triglycerides corticosteroid dosage, BMI, and SLEDAI has been found, thus suggesting that leptin could play a role in SLErelated cardiovascular diseases [131,132]. A relationship between leptin and lupus-disease-related factors has been also extensively characterized. Indeed, patients with SLE display increased concentrations of leptin and these concentrations are associated with insulin resistance, BMI, and CRP, in these patients [124]. Furthermore leptin has been shown to promote Th1 responses in normal human CD4+ T cells and in (NZB XNZW) F1 lupus-prone mice, by inducing RORγ transcription, whereas, on the contrary, its neutralization in those autoimmune-prone mice inhibits Th17 responses thus suggesting an important role in the pathogenesis of SLE [44]. Conversely, fasting induced hypoleptinemia [133] or leptin-deficient mice [134] exhibit decreased Th17 cells and higher Treg cells. Finally, it has been also recently shown that leptin can also promote T-cell survival by modulating T-cell apoptosis via an increased expression of Bcl-2 and can favor the proliferation of autoreactive T-cells in mice that carry an autoreactive T-cell repertoire, including NZB/W lupus-prone mice [135].

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Leptin and autoimmune diabetes

Diabetes is a group of metabolic diseases characterized by dysregulation of glucose metabolism, resulting from defects in insulin secretion, insulin action, or both; it leads to chronic

Please cite this article as: Procaccini C, et al, Leptin in autoimmune diseases, Metabolism (2014), http://dx.doi.org/10.1016/j. metabol.2014.10.014

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hyperglycemia and subsequent acute and chronic complications. It has traditionally been subdivided into T1D a childhood acute disorder characterized by autoimmune destruction of insulin-secreting β-cells, and T2D, a slow-onset, middle-life disorder presenting with insulin resistance and features of metabolic syndrome, including overweightness [136,137]. T1D is the most common (90%) type of diabetes in children and adolescent. Its incidence is increasing by approximately 4% per year [138]. Recent evidence has suggested that adipokines may also have a crucial role in the relationship between T1D and obesity, indeed leptin and adiponectin are two major insulin sensitizing mediators and regulate glucose metabolism through various mechanisms, including promotion of insulin secretion and storage of glucose, inhibition of glucagon secretion and hepatic gluconeogenesis [15,139]. It is now well established that leptin is also involved in spontaneous autoimmune disease such as T1D in the non-obese diabetic (NOD) mice. Leptin, indeed, accelerates the disease onset and progression by stimulating autoimmune destruction of β-cells and significantly increases IFN-γ production in peripheral Tcells [17]. Interestingly, a recent study has shown that a spontaneous mutation of the LepR in normally T1D-prone NOD mice (named LepRdb5J mice) suppresses T1D development in the NOD mice, by inhibiting activation of Tconv cells, thus demonstrating the important role of leptin signaling in the disease pathogenesis [140,141]. Distinctions between T1D and T2D are becoming increasingly vague both from the clinical and etiological point of view. One common point has been recently noted and identified: obesity has experienced the same dramatic increase as diabetes in recent decades [142], and is found as a common characteristic in the overlapping forms of diabetes mentioned above. Indeed in the “Accelerator Hypothesis” [143], it has been postulated that T1D and T2D are the same disorder of insulin resistance set against different genetic background. Both diseases are distinguishable only by their rate of β-cell loss and the “accelerators” responsible for such phenomenon; at the end, all diabetes progress to a final insulin-dependent state. This hypothesis puts overweightness at the heart of the pathogenesis of T1D in a continuum with T2D [143]. According to recent studies, an important role in the pathogenic processes and on the occurrence of T1D is played by the influence of maternal weight and weight gain during pregnancy, birthweight, weight gain in the early years of life, or childhood obesity [144]. A higher risk of diabetes was seen with increased birthweight [145], whereas calorie restriction during pregnancy leads to reduced birthweight and lower risk of diabetes in mice at 24 weeks [146,147]. In this context, longitudinal growth analysis in pre-diabetic T1D indicated increased BMI in the first year of life and an increased growth in length in the next 2 years. These heavier and taller children presented with autoantibodies against pancreatic islet tyrosine phosphatases at diagnosis many years later [148]. Insulin resistance is a function of fat mass, and increasing body weight in the industrialized world has been accompanied by earlier presentation of T2D, supporting the hypothesis that the age at presentation of T1D is associated with fatness [149–152]. The role of environmental factors in the incidence of T1D has been shown in the study by Hermann et al. [153], in which the authors demonstrated that the contribution of high

susceptibility genes to the development of T1D has diminished over the past generation, due to an increasing environmental pressure, which resulted in a higher disease progression rate especially in subjects with protective HLA genotypes. Other evidence indicated that insulin resistance precedes the onset of T1D [154,155] and among children at risk, those with the highest insulin resistance at baseline are those most likely to develop T1D [156]. Finally in twin studies with the same genetic risk of T1D development, Hawa et al. [157] have shown that children who developed disease had higher insulin resistance and lower β-cell reserve than those who did not. There are also controversial studies which support the protective role of leptin in the pathogenesis of diabetes [158– 163]. Indeed, Perry et al. demonstrate that leptin deficiency in T1D triggers a cascade of neuroendocrine events that involve an HPA-mediated increase in gluconeogenic and ketogenic substrate, leading to hyperglycemia and ketoacidosis [159]. Moreover, in ob/ob diabetic rats, systemic administration of leptin rapidly reversed ketoacidosis and normalized blood glucose concentration by decreasing the delivery of glycerol and fatty acids to the liver. In addition, leptin reduced the availability of acetyl-CoA which is an inhibitor of the conversion of pyruvate to glucose. These effects did not change plasma insulin, glucagon concentrations or the expression of gluconeogenic enzymes in the liver, indicating a new mechanism for leptin in regulating glucose homeostasis [158,159]. In line with this evidence Yu et al. showed that leptin reverses the catabolic consequences of total lack of insulin in insulin-deficient rodents, potentially by suppressing glucagon action on liver and enhancing the insulinomimetic actions of IGF-1 on skeletal muscle [160]. Parallel results have been obtained in another study [161] showing that in non-obese diabetic mice with uncontrolled type 1 diabetes, leptin therapy alone or combined with low-dose insulin reverses the catabolic state through suppression of hyperglucagonemia, by normalizing several hepatic intermediary metabolites and lowering lipogenic and cholesterologenic transcription factors and enzymes. Moreover, in another animal model of diabetes (virally induced type 1 diabetes in BB rats), it has been shown that leptin may prevent or suppress the autoreactive destruction of beta cells, by preventing rapid weight loss and diabetic ketoacidosis, and temporarily restoring euglycemia. The authors also showed that leptin treatment prolonged the survival of syngeneic islets transplanted into diabetic BBDR rats, suggesting that leptin could act as a potential adjunct therapeutic agent for treatment of T1D [162].

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Leptin and psoriasis

Pso is a chronic cutaneous immune-mediated disease that affects around 1–3% of the adult population, in which the most prominent microscopic abnormality is the hyperproliferation and altered differentiation of keratinocytes. Its pathophysiology involves genetic and environmental factors together with immune disturbances. Cutaneous lesions are characterized by very well circumscribed scaling papules and plaques that are typically distributed symmetrically on the knees, elbows, scalp, genitals, and trunk [164,165]. The role and influence of fat tissue and adipokines, including leptin, in the pathogenesis of Pso has

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been studied [166]. Recent papers [167,168] have demonstrated that the risk of psoriasis is directly related to BMI and those patients with obesity are likely to have severe psoriasis. Although psoriasis and obesity share similar mediators of inflammation, such as TNF-α and IL-6, the precise biological mechanisms of the relationship between leptin and psoriasis remains still unclear [169]. Leptin is predominantly synthesized in adipocytes, including subcutaneous adipocytes [170], however, synthesis of leptin and its receptors has also been detected in human and mice fibroblasts and keratinocytes [171–174]. Wang et al. showed increasing leptin levels in patients with psoriasis compared to healthy controls [175], on the contrary, Johnston et al. demonstrated that in patients with psoriasis leptin levels were not higher than controls but rather leptin was able to increase several inflammatory cytokines such as CXCL8 and TNF-α. Leptin also increased secretion of the growth factor amphiregulin by ex vivo-cultured lesional psoriasis skin [176]. In addition, the levels of leptin in psoriasis have been shown to be increased as the severity of psoriasis increased [177,178]. Indeed, it has been showed that serum leptin levels, tissue leptin and leptin receptor expression were significantly higher in patients with severe psoriasis than patients with mild–moderate psoriasis and controls. Specifically authors demonstrated that serum leptin levels showed a positive correlation with Psoriasis Area and Severity Index (PASI) and involved body surface area in patients with psoriasis. In addition, serum leptin levels, tissue leptin and leptin receptor expression showed a positive correlation with disease duration in patients with psoriasis [177], suggesting that leptin might serve as a marker of severity in psoriasis and also may be a pathogenetic cofactor contributing to chronicity of the disease. Other authors showed that hyperleptinemia in psoriasis may also contribute to metabolic syndrome [179].

9.

Leptin and autoimmune thyroiditis

AT diseases encompass a spectrum of disorders characterized by an autoimmune attack on the thyroid gland, including HT, Grave's disease and post-partum thyroiditis. HT is the most common autoimmune disease [180], the most common endocrine disorder [181], as well as the most common cause of hypothyroidism [182]. It is an organ-specific autoimmune disease characterized by the presence of a goiter with lymphocytic infiltration, associated with serum thyroid antibodies and systemic manifestation related to hypothyroidism [183]. HT is a multifactorial disease, resulting from a complex interaction between genetic and environmental factors, such as excess iodine, synthetic chemicals, or infections [184,185]. Thyroid function has been extensively investigated in obese subjects. Indeed, elevated serum thyroid-stimulating hormone (thyrotropin, TSH) concentration is frequently reported in obese individuals and positively correlated with BMI [186,187]. Indeed leptin level and leptin/BMI ratio have been shown to be higher in postpartum thyroiditis patients than in controls, during the first postpartum year [188]. Moreover, in Graves' disease, thyroid hormones have been shown to increase serum leptin levels during suppression of beta-adrenergic receptors [189] and Erickson et al. have also shown that leptin expression was 6 to 37 times greater in the orbital fibroblasts from Graves'

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ophthalmopathy patients when compared to control subjects [190]. Besides these hormonal changes associated with obesity, some studies have suggested that obese people could also be more prone to develop HT [191–193] and the fact that treatment with T4 decreases leptin levels [191], without affecting BMI, strongly indicates an association between leptin and thyroid status. In light of these findings, a recent cross-sectional study has reported a greater prevalence of hypothyroidism and HTrelated autoantibodies among obese individuals, correlated with increased leptin levels [192]. According to the authors, leptin levels, which are positively associated with serum TSH and inversely with FT4 levels, together with the female sex, might well represent a predictor of autoimmune thyroiditis. Another study [193] reported on a huge cohort study that childhood weight gain and childhood overweightness conferred a slightly increased risk of HT development at the age of 60–64 years, particularly in women. Finally, Wang et al. have recently shown that the higher leptin levels found in HT patients, associated with an increased percentage of Th17 cells [194], which are suggested to be involved in the pathogenesis of HT [195,196].

10.

Concluding remarks

Since its discovery in 1994, leptin has attracted increasing interest in the scientific community for its pleiotropic functions. In immune cells, leptin acts as a proinflammatory cytokine that promotes Th1 responses on one side and inhibits Treg cell expansion on the other, setting the basis for exaggerated, immune-inflammatory responses to altered self or nonself and leading to autoimmunity in subjects with autoimmunity risk factors. Recent studies from Fontana et al. [197] have shown that caloric restriction and consequent lowering of serum leptin are able in humans to significantly reduce inflammatory parameters [198]. In view of its influence on food intake and metabolism, leptin situates at the interface between metabolism and immunity in modulating not only inflammation but also immune and autoimmune reactivity. Recently, molecules with orexigenic activity such as ghrelin and NPY [13,199] have been shown to mediate effects opposite to leptin in the hypothalamic control of food intake and on peripheral immune responses. For example, ghrelin blocks leptin-induced secretion of proinflammatory cytokines by human T cells, and NPY ameliorates clinical score and progression of EAE [13,199]. Thus, several metabolic regulators might broadly influence vital functions not only by tuning caloric balance but also by affecting immune responses both in physiological and pathological conditions.

Author contributions All the authors contributed in writing this review.

Acknowledgements G.M. is supported by grants from Fondazione Italiana Sclerosi Multipla (FISM) 2012/R/11, the European Union IDEAS Programme

Please cite this article as: Procaccini C, et al, Leptin in autoimmune diseases, Metabolism (2014), http://dx.doi.org/10.1016/j. metabol.2014.10.014

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European Research Council Starting Grant “menTORingTregs” no. 310496, Grant CNR “Medicina Personalizzata” and FIRB-MERIT no. RBNE08HWLZ_15. This work is dedicated to the memory of Eugenia Papa and Serafino Zappacosta.

Conflict of interest

[19] [20]

[21]

The authors declare no competing financial interests.

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