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

ABSTRACT: The immune system plays an instrumental role in obesity and insulin resistance. Here, we unravel the role of the costimulatory molecule CD40 and its signaling intermediates, TNF receptor-associated factors (TRAFs), in diet-induced obesity (DIO). Although not exhibiting increased weight gain, male CD40(-/-) mice in DIO displayed worsened insulin resistance, compared with wild-type mice. This worsening was associated with excessive inflammation of adipose tissue (AT), characterized by increased accumulation of CD8(+) T cells and M1 macrophages, and enhanced hepatosteatosis. Mice with deficient CD40-TRAF2/3/5 signaling in MHCII(+) cells exhibited a similar phenotype in DIO as CD40(-/-) mice. In contrast, mice with deficient CD40-TRAF6 signaling in MHCII(+) cells displayed no insulin resistance and showed a reduction in both AT inflammation and hepatosteatosis in DIO. To prove the therapeutic potential of inhibition of CD40-TRAF6 in obesity, DIO mice were treated with a small-molecule inhibitor that we designed to specifically block CD40-TRAF6 interactions; this compound improved insulin sensitivity, reduced AT inflammation, and decreased hepatosteatosis. Our study reveals that the CD40-TRAF2/3/5 signaling pathway in MHCII(+) cells protects against AT inflammation and metabolic complications associated with obesity whereas CD40-TRAF6 interactions in MHCII(+) cells aggravate these complications. Inhibition of CD40-TRAF6 signaling by our compound may provide a therapeutic option in obesity-associated insulin resistance.

SUBMITTER: Chatzigeorgiou A

PROVIDER: S-EPMC3932883 | biostudies-other | 2014 Feb

REPOSITORIES: biostudies-other

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

Chatzigeorgiou Antonios A Seijkens Tom T Zarzycka Barbara B Engel David D Poggi Marjorie M van den Berg Susan S van den Berg Sjoerd S Soehnlein Oliver O Winkels Holger H Beckers Linda L Lievens Dirk D Driessen Ann A Kusters Pascal P Biessen Erik E Garcia-Martin Ruben R Klotzsche-von Ameln Anne A Gijbels Marion M Noelle Randolph R Boon Louis L Hackeng Tilman T Schulte Klaus-Martin KM Xu Aimin A Vriend Gert G Nabuurs Sander S Chung Kyoung-Jin KJ Willems van Dijk Ko K Rensen Patrick C N PC Gerdes Norbert N de Winther Menno M Block Norman L NL Schally Andrew V AV Weber Christian C Bornstein Stefan R SR Nicolaes Gerry G Chavakis Triantafyllos T Lutgens Esther E

Proceedings of the National Academy of Sciences of the United States of America 20140203 7

The immune system plays an instrumental role in obesity and insulin resistance. Here, we unravel the role of the costimulatory molecule CD40 and its signaling intermediates, TNF receptor-associated factors (TRAFs), in diet-induced obesity (DIO). Although not exhibiting increased weight gain, male CD40(-/-) mice in DIO displayed worsened insulin resistance, compared with wild-type mice. This worsening was associated with excessive inflammation of adipose tissue (AT), characterized by increased ac ...[more]

PMID: 24492375

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Project description:BackgroundDisrupting the costimulatory CD40-CD40L dyad reduces atherosclerosis, but can result in immune suppression. The authors recently identified small molecule inhibitors that block the interaction between CD40 and tumor necrosis factor receptor-associated factor (TRAF) 6 (TRAF-STOPs), while leaving CD40-TRAF2/3/5 interactions intact, thereby preserving CD40-mediated immunity.ObjectivesThis study evaluates the potential of TRAF-STOP treatment in atherosclerosis.MethodsThe effects of TRAF-STOPs on atherosclerosis were investigated in apolipoprotein E deficient (Apoe-/-) mice. Recombinant high-density lipoprotein (rHDL) nanoparticles were used to target TRAF-STOPs to macrophages.ResultsTRAF-STOP treatment of young Apoe-/- mice reduced atherosclerosis by reducing CD40 and integrin expression in classical monocytes, thereby hampering monocyte recruitment. When Apoe-/- mice with established atherosclerosis were treated with TRAF-STOPs, plaque progression was halted, and plaques contained an increase in collagen, developed small necrotic cores, and contained only a few immune cells. TRAF-STOP treatment did not impair "classical" immune pathways of CD40, including T-cell proliferation and costimulation, Ig isotype switching, or germinal center formation, but reduced CD40 and β2-integrin expression in inflammatory monocytes. In vitro testing and transcriptional profiling showed that TRAF-STOPs are effective in reducing macrophage migration and activation, which could be attributed to reduced phosphorylation of signaling intermediates of the canonical NF-κB pathway. To target TRAF-STOPs specifically to macrophages, TRAF-STOP 6877002 was incorporated into rHDL nanoparticles. Six weeks of rHDL-6877002 treatment attenuated the initiation of atherosclerosis in Apoe-/- mice.ConclusionsTRAF-STOPs can overcome the current limitations of long-term CD40 inhibition in atherosclerosis and have the potential to become a future therapeutic for atherosclerosis.

Dataset Information

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

Publications

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

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