Deficiency for Costimulatory Receptor 4-1BB Protects Against Obesity-Induced Inflammation and Metabolic Disorders

Kim, Chu-Sook; Kim, Jae Geun; Lee, Byung-Ju; Choi, Myung‐Sook; Choi, Hye-Sun; Kawada, Teruo; Lee, Ki‐Up; Yu, Rina

doi:10.2337/db10-1805

Cited by 49 publications

(52 citation statements)

References 53 publications

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“…Moreover, AT inflammation and hepatosteatosis were decreased, whereas glucose tolerance was improved (49). Counterintuitively, antibody-mediated stimulation of CD137 also reduced body weight, adiposity, and IR (67).…”

Section: Cd137-cd137lmentioning

confidence: 88%

“…Hence, costimulatory interactions are likely to mediate a rather broad crosstalk between innate and adaptive immunity during the pathogenesis of obesity and its related complications. Multiple costimulatory dyads of the B7 family and the tumor necrosis factor superfamilies are expressed on cell types involved in obesity-associated inflammation, and some have been identified as critical contributors to the pathogenesis of obesity (Table 1) (32,(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51).…”

Section: T-cell Antigen-presenting Cell Interactions In Obesitymentioning

confidence: 99%

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Immune Cell Crosstalk in Obesity: A Key Role for Costimulation?

et al. 2014

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In the past two decades, numerous experimental and clinical studies have established the importance of inflammation and immunity in the development of obesity and its metabolic complications, including insulin resistance and type 2 diabetes mellitus. In this context, T cells orchestrate inflammatory processes in metabolic organs, such as the adipose tissue (AT) and liver, thereby mediating obesity-related metabolic deterioration. Costimulatory molecules, which are present on antigen-presenting cells and naïve T cells in the AT, are known to mediate the crosstalk between the adaptive and innate immune system and to direct T-cell responses in inflammation. In this Perspectives in Diabetes article, we highlight the newest insights in immune cell interactions in obesity and discuss the role of costimulatory dyads in its pathogenesis. Moreover, the potential of therapeutic strategies that target costimulatory molecules in the metabolic syndrome is explored.

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Section: Cd137-cd137lmentioning

confidence: 88%

Section: T-cell Antigen-presenting Cell Interactions In Obesitymentioning

confidence: 99%

Immune Cell Crosstalk in Obesity: A Key Role for Costimulation?

et al. 2014

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“…Indeed, we and others previously demonstrated a requirement for the costimulatory molecules CD40L and 4-1BB to maintain adipose tissue inflammation in mice. 16,23,24 Surprisingly, Guo et al 18 previously suggested a protective role for the CD40 receptor in adipose tissue inflammation. In their study, CD40 −/− mice exhibited a hyperinflammatory phenotype with increased immune cell accumulation, elevated cytokine levels, hepatic steatosis, insulin resistance, and glucose intolerance.…”

Section: Discussionmentioning

confidence: 99%

Coinhibitory Suppression of T Cell Activation by CD40 Protects Against Obesity and Adipose Tissue Inflammation in Mice

et al. 2014

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T he metabolic syndrome comprises a cluster of risk factors, including obesity, insulin resistance, hepatic steatosis, and dyslipidemia. It is associated with a variety of cardiovascular diseases such as atherosclerosis, myocardial infarction, and stroke.1 Chronic, low-grade inflammation in key metabolic organs such as the liver and visceral adipose tissue (VAT) Background-Costimulatory cascades such as the CD40L-CD40 dyad enhance immune cell activation and inflammation during atherosclerosis. Here, we tested the hypothesis that CD40 directly modulates traits of the metabolic syndrome in diet-induced obesity in mice. Methods and Results-To induce the metabolic syndrome, wild-type or CD40 −/− mice consumed a high-fat diet for 20 weeks. Unexpectedly, CD40−/− mice exhibited increased weight gain, impaired insulin secretion, augmented accumulation of inflammatory cells in adipose tissue, and enhanced proinflammatory gene expression. This proinflammatory and adverse metabolic phenotype could be transplanted into wild-type mice by reconstitution with CD40-deficient lymphocytes, indicating a major role for CD40 in T or B cells in this context. Conversely, therapeutic activation of CD40 signaling by the stimulating antibody FGK45 abolished further weight gain during the study, lowered glucose levels, improved insulin sensitivity, and suppressed adipose tissue inflammation. Mechanistically, CD40 activation decreased the expression of proinflammatory cytokines in T cells but not in B cells or macrophages. Finally, repopulation of lymphocyte-free Rag1 −/− mice with CD40 −/− T cells provoked dysmetabolism and inflammation, corroborating a protective role of CD40 on T cells in the metabolic syndrome. Finally, levels of soluble CD40 showed a positive association with obesity in humans, suggesting clinical relevance of our findings. Conclusions-We present the surprising finding that CD40 deficiency on T cells aggravates whereas activation of CD40 signaling improves adipose tissue inflammation and its metabolic complications. Therefore, positive modulation of the CD40 pathway might describe a novel therapeutic concept against cardiometabolic disease. T-regulatory (T reg ) cells, CD8 + T cells, and related chemokines and cytokines such as RANTES (regulated on activation normal T cell expressed and secreted) and interferon-γ (IFNγ) colocalize within the inflammatory cell compartment in adipose tissue. 7 In lean adipose tissue, the vast majority of T lymphocytes share features of anti-inflammatory, interleukin (IL)-13-, IL-4-, and IL-10-secreting Th2 or T reg cells. 8In obesity, proinflammatory Th1 cells expressing IFNγ overwhelm Th2 cells.9 Th1 cells, in turn, activate proinflammatory cytokine-secreting macrophages and promote their conversion from M2-like, IL-10-secreting, alternatively activated macrophages to classically activated, M1-like macrophages. 10,11Despite description of the kinetics of cellular infiltration and the associated cytokine/chemokine profiles during the development of obesity, the underlying cause modu...

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“…For example, interaction between 4-1BB and 4-1BBL on endothelial cells and macrophages is involved in vascular inflammation [14, 15], and interaction between the two molecules on epithelial cells and natural killer cells is involved in renal ischemia-reperfusion injury [16]. We previously showed that expression of 4-1BB and 4-1BBL was upregulated in adipose tissue that was inflamed due to obesity, and that ablation of 4-1BB reduced adipose inflammation [17]. Hence, we hypothesized that interaction between 4-1BB and 4-1BBL on adipose cells and immune cells such as macrophages plays a role in adipose inflammation in obesity.…”

Section: Introductionmentioning

confidence: 99%

4-1BB/4-1BBL Interaction Promotes Obesity-Induced Adipose Inflammation by Triggering Bidirectional Inflammatory Signaling in Adipocytes/Macrophages

Kim

Goto

et al. 2012

Mediators of Inflammation

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Obesity-induced adipose inflammation is characterized by recruitment of macrophages to adipose tissue and release of inflammatory cytokines. 4-1BB, a costimulatory receptor, modulates inflammatory processes through interaction with its ligand 4-1BBL on immune cell surfaces. In this study, we examined whether a 4-1BB/4-1BBL interaction between adipocytes and macrophages participates in obesity-induced adipose inflammation. We found that 4-1BB was expressed on adipocytes and was upregulated by obesity-related factors, which also enhanced 4-1BBL expression on macrophages. 4-1BB and/or 4-1BBL agonists, respectively, activated inflammatory signaling molecules (MAPK/IκBα and MAPK/Akt) in adipocytes and macrophages and enhanced the release of inflammatory cytokines (MCP-1, TNF-α, and IL-6). Moreover, disruption of the 4-1BB/4-1BBL interaction decreased the release of inflammatory cytokines from contact cocultured adipocytes/macrophages. These findings indicate that 4-1BB/4-1BBL-mediated bidirectional signaling in adipocytes/macrophages promotes adipose inflammation. 4-1BB and 4-1BBL may be useful targets for protection against obesity-induced adipose inflammation.

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Deficiency for Costimulatory Receptor 4-1BB Protects Against Obesity-Induced Inflammation and Metabolic Disorders

Cited by 49 publications

References 53 publications

Immune Cell Crosstalk in Obesity: A Key Role for Costimulation?

Immune Cell Crosstalk in Obesity: A Key Role for Costimulation?

Coinhibitory Suppression of T Cell Activation by CD40 Protects Against Obesity and Adipose Tissue Inflammation in Mice

4-1BB/4-1BBL Interaction Promotes Obesity-Induced Adipose Inflammation by Triggering Bidirectional Inflammatory Signaling in Adipocytes/Macrophages

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