Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance

Chatzigeorgiou, Antonios; Seijkens, Tom; Zarzycka, Barbara; Engel, David; Poggi, Marjorie; Berg, Susan; Berg, Sjoerd van den; Soehnlein, Oliver; Winkels, Holger; Beckers, Linda; Lievens, Dirk; Driessen, Ann; Kusters, Pascal; Biessen, Erik A. L.; García‐Martín, Rubén; Ameln, Anne Klotzsche–von; Gijbels, Marion J.J.; Noelle, Randolph J.; Boon, Louis; Hackeng, Tilman M.; Schulte, Klaus–Martin; Xu, Aimin; Vriend, Gert; Nabuurs, Sander B.; Chung, Kyoung‐Jin; Dijk, Ko Willems van; Rensen, Patrick C.N.; Gerdes, Norbert; Winther, Menno P.J. de; Block, Norman L.; Schally, Andrew V.; Weber, Christian; Bornstein, Stefan R.; Nicolaes, Gerry A. F.; Chavakis, Triantafyllos; Lutgens, Esther

doi:10.1073/pnas.1400419111

Cited by 112 publications

(143 citation statements)

References 26 publications

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“…CD40 contains a distal binding site for TRAF2, 3, and 5 and a proximal binding site for TRAF6. When obesity was induced in mice with a deficiency in the CD40-TRAF2/3/5 interaction in MHCII + cells, a similar phenotype as in obese CD40 2/2 mice was observed (46). CD40-TRAF2/3/5 2/2 mice exhibited an aggravation of AT inflammation, IR, and hepatosteatosis (46).…”

Section: /2mentioning

confidence: 87%

“…When obesity was induced in mice with a deficiency in the CD40-TRAF2/3/5 interaction in MHCII + cells, a similar phenotype as in obese CD40 2/2 mice was observed (46). CD40-TRAF2/3/5 2/2 mice exhibited an aggravation of AT inflammation, IR, and hepatosteatosis (46). Of note, deficiency of CD40-TRAF6 interactions in MHCII + cells instead protected mice against these obesity-induced aberrations (46).…”

Section: /2mentioning

confidence: 92%

“…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%

“…mice accompanied by an M1-biased inflammatory response, as indicated by higher numbers of M1 macrophages and increased expression of TNF, IL-6, and IL-12 (46). To understand these contradictory results, we recently explored the involvement of various signaling pathways induced upon CD40 activation.…”

Section: /2mentioning

confidence: 99%

“…CD40-TRAF2/3/5 2/2 mice exhibited an aggravation of AT inflammation, IR, and hepatosteatosis (46). Of note, deficiency of CD40-TRAF6 interactions in MHCII + cells instead protected mice against these obesity-induced aberrations (46). To exploit this potential therapeutic target, we developed a small molecule inhibitor of the CD40-TRAF6 interaction, which reduced AT inflammation, IR, and hepatosteatosis in DIO mice (46).…”

Section: /2mentioning

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: /2mentioning

confidence: 87%

Section: /2mentioning

confidence: 92%

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

confidence: 99%

Section: /2mentioning

confidence: 99%

Section: /2mentioning

confidence: 99%

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

et al. 2014

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Dual role of B7 costimulation in obesity-related nonalcoholic steatohepatitis and metabolic dysregulation

et al. 2014

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The low-grade inflammatory state present in obesity contributes to obesity-related metabolic dysregulation, including nonalcoholic steatohepatitis (NASH) and insulin resistance. Intercellular interactions between immune cells or between immune cells and hepatic parenchymal cells contribute to the exacerbation of liver inflammation and steatosis in obesity. The costimulatory molecules, B7.1 and B7.2, are important regulators of cell-cell interactions in several immune processes; however, the role of B7 costimulation in obesity-related liver inflammation is unknown. Here, diet-induced obesity (DIO) studies in mice with genetic inactivation of both B7.1 and B7.2 (double knockout; DKO) revealed aggravated obesity-related metabolic dysregulation, reduced insulin signalling in the liver and adipose tissue (AT), glucose intolerance, and enhanced progression to steatohepatitis resulting from B7.1/B7.2 double deficiency. The metabolic phenotype of B7.1/B7.2 double deficiency upon DIO was accompanied by increased hepatic and AT inflammation, associated with largely reduced numbers of regulatory T cells (Tregs) in these organs. In order to assess the role of B7 costimulation in DIO in a non-Treg-lacking environment, we performed antibody (Ab)-mediated inhibition of B7 molecules in wild-type mice in DIO. Antibodyblockade of both B7.1 and B7.2 improved the metabolic phenotype of DIO mice, which was linked to amelioration of hepatic steatosis and reduced inflammation in liver and AT. Conclusion: Our study demonstrates a dual role of B7 costimulation in the course of obesity-related sequelae, particularly NASH. The genetic inactivation of B7.1/B7.2 deteriorates obesity-related liver steatosis and metabolic dysregulation, likely a result of the intrinsic absence of Tregs in these mice, rendering DKO mice a novel murine model of NASH. In contrast, inhibition of B7 costimulation under conditions where Tregs are present may provide a novel therapeutic approach for obesityrelated metabolic dysregulation and, especially, NASH. (HEPATOLOGY 2014;60:1196-1210 O besity is associated with low-grade inflammation, liable for the development of insulin resistance (IR), type 2 diabetes, and nonalcoholic steatohepatitis (NASH). Immune cells of both innate and adaptive immunity are implicated in this process and contribute to the development of

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Hepatic leukocyte immunoglobulin‐like receptor B4 (LILRB4) attenuates nonalcoholic fatty liver disease via SHP1‐TRAF6 pathway

Jiang

Dai

et al. 2018

Hepatology

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Nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent liver pathology characterized by hepatic steatosis and commonly accompanied by systematic inflammation and metabolic disorder. Despite an accumulating number of studies, no pharmacological strategy is available to treat this condition in the clinic. In this study, we applied extensive gain‐ and loss‐of‐function approaches to identify the key immune factor leukocyte immunoglobulin‐like receptor B4 (LILRB4) as a negative regulator of NAFLD. The hepatocyte‐specific knockout of LILRB4 (LILRB4‐HKO) exacerbated high‐fat diet–induced insulin resistance, glucose metabolic imbalance, hepatic lipid accumulation, and systematic inflammation in mice, whereas LILRB4 overexpression in hepatocytes showed a completely opposite phenotype relative to that of LILRB4‐HKO mice when compared with their corresponding controls. Further investigations of molecular mechanisms demonstrated that LILRB4 recruits SHP1 to inhibit TRAF6 ubiquitination and subsequent inactivation of nuclear factor kappa B and mitogen‐activated protein kinase cascades. From a therapeutic perspective, the overexpression of LILRB4 in a genetic model of NAFLD, ob/ob mice, largely reversed the inherent hepatic steatosis, inflammation, and metabolic disorder. Conclusion: Targeting hepatic LILRB4 to improve its expression or activation represents a promising strategy for the treatment of NAFLD as well as related liver and metabolic diseases. (Hepatology 2018;67:1303‐1319)

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Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance

Cited by 112 publications

References 26 publications

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

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

Dual role of B7 costimulation in obesity-related nonalcoholic steatohepatitis and metabolic dysregulation

Hepatic leukocyte immunoglobulin‐like receptor B4 (LILRB4) attenuates nonalcoholic fatty liver disease via SHP1‐TRAF6 pathway

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