Leptin Signaling Deficiency Impairs Humoral and Cellular Immune Responses and Attenuates Experimental Arthritis

Busso, Nathalie; So, Alexander; Chobaz-Péclat, Veronique; Morard, Carole; Martinez-Soría, Eduardo; Talabot-Ayer, Dominique; Gabay, Cem

doi:10.4049/jimmunol.168.2.875

Cited by 297 publications

(253 citation statements)

References 47 publications

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“…These findings indicate that the functional defects in DC populations are directly caused by the leptin-signaling deficiency in db/db mice. Abnormalities in the immune system have been reported in db/db mice, which suggests that the immune system might be involved in the pathogenesis of diabetes [29,30]. Recent studies have shown that leptin-deficient ob/ob mice are resistant to induction of experimental autoimmune encephalomyelitis, and leptin blockade inhibits T cell autoreactivity and slows disease progression in SJL/J mice [31,32].…”

Section: Discussionmentioning

confidence: 99%

Involvement of leptin signaling in the survival and maturation of bone marrow‐derived dendritic cells

et al. 2006

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Previous studies demonstrated that lymphocyte development is impaired in leptin receptor (Ob-R)-deficient db/db mice. However, it remains unclear whether or not leptin signaling plays a physiological role in dendritic cell (DC) development and function. In this study, we first detected Ob-R expression in murine DC. Using db/db mice at a pre-diabetic stage, we demonstrate that the total number of DC generated from bone marrow (BM) cultures is significantly lower than in WT controls. Similarly, selective blockade of leptin with a soluble mouse Ob-R chimera (Ob-R:Fc) inhibited DC generation in wild-type BM cultures. The reduced DC yield in db/db BM culture was attributed to significantly increased apoptosis, which was associated with dysregulated expression of Bcl-2 family genes. Moreover, db/db DC displayed markedly reduced expression of co-stimulatory molecules and a Th2-type cytokine profile, with a poor capacity to stimulate allogeneic T cell proliferation. Consistent with their impaired DC phenotype and function, db/db DC showed significantly down-regulated activities of the PI3K/Akt pathway as well as STAT-3 and IjB-a. In conclusion, our findings demonstrate the involvement of leptin signaling in DC survival and maturation.See accompanying commentary: http://dx

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Section: Discussionmentioning

confidence: 99%

Involvement of leptin signaling in the survival and maturation of bone marrow‐derived dendritic cells

et al. 2006

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“…69 The milder form of antigen-induced arthritis seen in ob/ob and db/db mice, as compared with their controls, was accompanied by decreased synovial levels of IL-1 and TNF-a and a reduced proliferative response to antigen by lymph node cells in vitro. 57 RA is a chronic systemic inflammatory disease of the synovial tissue.…”

Section: Leptin and Autoimmunity M Vadacca Et Al 207mentioning

confidence: 94%

Leptin in immuno-rheumatological diseases

et al. 2011

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Leptin is one of the most important hormones secreted by adipocytes, with a variety of physiological roles related to the control of metabolism and energy homeostasis. Since its discovery in 1994, leptin has attracted increasing interest in the scientific community for its pleiotropic actions. One of these functions is the relationship between nutritional status and immune competence. It structurally resembles proinflammatory cytokines, such as IL-6 and IL-12. The cytokine-like structural characteristic of leptin is implicative of its function in regulating immune responses. The role of leptin in regulating immune responses has been assessed in vitro as well as in clinical studies. It has been shown that disease conditions of reduced leptin production are associated with increased infection susceptibility. Conversely, immune-mediated disorders, such as autoimmune diseases, are associated with the increased secretion of leptin and the production of proinflammatory pathogenic cytokines. In this paper, we review the most recent advances of the role of leptin in immune-rheumatological diseases, and we discuss whether strategies aimed at modifying leptin levels could represent innovative and therapeutic tools for autoimmune disorders. Keywords: adipokines; autoimmune diseases; leptin; rheumatic diseases INTRODUCTIONThe existence of a factor secreted by white adipose tissue (WAT), which acts to control feeding, weight and WAT mass, was first proposed by Kennedy 1 and is supported by monogenic mutations resulting in obesity. [2][3][4] WAT is composed of adipocytes filled mainly with triacylglycerol and embedded in loose connective tissue containing adipocyte precursors, fibroblasts, immune and other cells. Obesity, the condition that originally motivated the research on WAT, is characterized by low-grade systemic inflammation. It is thought that excess WAT can contribute to the maintenance of obesity through inflammation-inducing lipotoxicity by secreting factors that stimulate the synthesis of inflammatory agents in other organs and by secreting inflammatory agents itself. 5 The current view of WAT states that it is an active contributor to body homeostasis by sending out and responding to signals that modulate appetite, energy expenditure, insulin sensitivity, the endocrine and reproductive systems, bone metabolism, inflammation and immunity. 6 Several findings have converged to indicate that adipocytes share certain properties with immune cells, such as complement activation 7 and proinflammatory cytokine production. 8 Fat cell precursors also share features with macrophages. Numerous genes that code for transcription factors, cytokines, inflammatory signaling molecules, and fatty acid transporters are essential for adipocyte biology and are also expressed and functional in macrophages. 9 Adipose tissue secrets a variety of factors: the term 'adipokine' is generally given to any protein that can be synthesized and secreted by adipocytes. Among these factors, only leptin and adiponectin (and possibly resistin, adipsi...

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“…Measurements of serum levels of anti-mBSA antibodies and T cell proliferation assays were performed as described previously (15).…”

Section: Methodsmentioning

confidence: 99%

Evaluation of protease‐activated receptor 2 in murine models of arthritis

Busso

Frasnelli

Feifel

et al. 2007

Arthritis & Rheumatism

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ObjectiveProtease‐activated receptor 2 (PAR‐2) activation has been linked to pro‐ and antiinflammatory cellular responses. We undertook this study to explore the importance of PAR‐2 activation in 4 murine models of arthritis and to analyze the expression of PAR‐2 in human arthritic synovium.MethodsZymosan‐induced arthritis (ZIA), K/BxN serum–induced arthritis, and Freund's complete adjuvant (CFA)–induced arthritis were generated in naive PAR‐2−/− mice and PAR‐2+/+ littermates. Antigen‐induced arthritis (AIA) was generated in immunized mice using methylated bovine serum albumin (mBSA). The severity of arthritis was assessed by clinical scoring, technetium uptake measurement, and histologic analysis. Immune responses to mBSA were also evaluated from AIA. The expression of PAR‐2 in synovial tissues from rheumatoid arthritis (RA) and osteoarthritis (OA) patients was compared.ResultsIn AIA, arthritis was significantly decreased in PAR‐2–deficient mice and was associated with decreased levels of anti‐mBSA IgG antibodies and lymph node cell proliferation. No difference in arthritis severity was seen in mice with ZIA, K/BxN serum–induced arthritis, and CFA‐induced arthritis. Synovial biopsy specimens from RA patients demonstrated significantly increased expression of PAR‐2 compared with those from OA patients.ConclusionPAR‐2 deficiency was found to modulate articular inflammation in murine models of arthritis that require prior immunization and was associated with reduced levels of anti‐mBSA IgG and lymph node cell proliferation in AIA. Expression of PAR‐2 in RA synovium was significantly higher than that in OA synovium, and this suggests that PAR‐2 is implicated in the pathogenesis of immune‐mediated forms of arthritis.

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Leptin Signaling Deficiency Impairs Humoral and Cellular Immune Responses and Attenuates Experimental Arthritis

Cited by 297 publications

References 47 publications

Involvement of leptin signaling in the survival and maturation of bone marrow‐derived dendritic cells

Involvement of leptin signaling in the survival and maturation of bone marrow‐derived dendritic cells

Leptin in immuno-rheumatological diseases

Evaluation of protease‐activated receptor 2 in murine models of arthritis

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