Dennis Wolf1, Felix Jehle1, Nathaly Anto Michel1, Eva Nora Bukosza1, Jennifer Rivera1, Yung Chih Chen1, Natalie Hoppe1, Bianca Dufner1, Alexandra Ortiz Rodriguez1, Christian Colberg1, Leandro Nieto1, Benjamin Rupprecht1, Ansgar Wiedemann1, Lisa Schulte1, Alexander Peikert1, Nicole Bassler1, Andrey Lozhkin1, Sonja Patricia Hergeth1, Peter Stachon1, Ingo Hilgendorf1, Florian Willecke1, Constantin von Zur Mühlen1, Dominik von Elverfeldt1, Christoph J Binder1, Peter Aichele1, Nerea Varo1, Mark A Febbraio1, Peter Libby1, Christoph Bode1, Karlheinz Peter2, Andreas Zirlik1. 1. From the Atherogenesis Research Group, University Heart Center (D.W., F.J., N.A.M., E.N.B., N.H., B.D., A.O.R., C.C., L.N., B.R., A.W., L.S., A.P., A.L., S.P.H., P.S., I.H., F.W., C.v.z.M., C.B., A.Z.) and Institute for Medical Microbiology and Hygiene, Department of Immunology (P.A.), University of Freiburg, Freiburg, Germany; Atherothrombosis and Vascular Biology (F.J., J.R., Y.C.C., C.C., N.B., K.P.) and Cellular and Molecular Metabolism (M.A.F.), Baker IDI Heart and Diabetes Institute, Melbourne, Australia; Department of Diagnostic Radiology Medical Physics, University Hospital Freiburg, Freiburg, Germany (D.v.E.); Department of Laboratory Medicine, Medical University of Vienna and Center for Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria (C.J.B.); Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain (N.V.); and Brigham and Women's Hospital, Cardiovascular Medicine, Harvard Medical School, Boston, MA (P.L.). 2. From the Atherogenesis Research Group, University Heart Center (D.W., F.J., N.A.M., E.N.B., N.H., B.D., A.O.R., C.C., L.N., B.R., A.W., L.S., A.P., A.L., S.P.H., P.S., I.H., F.W., C.v.z.M., C.B., A.Z.) and Institute for Medical Microbiology and Hygiene, Department of Immunology (P.A.), University of Freiburg, Freiburg, Germany; Atherothrombosis and Vascular Biology (F.J., J.R., Y.C.C., C.C., N.B., K.P.) and Cellular and Molecular Metabolism (M.A.F.), Baker IDI Heart and Diabetes Institute, Melbourne, Australia; Department of Diagnostic Radiology Medical Physics, University Hospital Freiburg, Freiburg, Germany (D.v.E.); Department of Laboratory Medicine, Medical University of Vienna and Center for Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria (C.J.B.); Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain (N.V.); and Brigham and Women's Hospital, Cardiovascular Medicine, Harvard Medical School, Boston, MA (P.L.). karlheinz.peter@bakeridi.edu.au.
Abstract
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.
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 CD40deficiency 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.
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