Dual role of B7 costimulation in obesity-related... : Hepatology (original) (raw)

Steatohepatitis/Metabolic Liver Disease

Chatzigeorgiou, Antonios1,2,3,4,*; Chung, Kyoung-Jin1,5,*; Garcia-Martin, Ruben1; Alexaki, Vasileia-Ismini1; Klotzsche-von Ameln, Anne1,5; Phieler, Julia1,4; Sprott, David1; Kanczkowski, Waldemar3; Tzanavari, Theodora6; Bdeir, Mohktar1; Bergmann, Sibylle2; Cartellieri, Marc7,8; Bachmann, Michael7,8; Nikolakopoulou, Polyxeni3; Androutsellis-Theotokis, Andreas3; Siegert, Gabriele2; Bornstein, Stefan R.3; Muders, Michael H.9; Boon, Louis10; Karalis, Katia P.3,6,11; Lutgens, Esther12,13; Chavakis, Triantafyllos1,2,3,4

From the 1 Department of Clinical Pathobiochemistry, Technische Universität Dresden, Dresden, Germany; 2Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany; 3Department of Medicine III, Technische Universität Dresden, Dresden, Germany; 4Paul Langerhans Institute, Dresden, Dresden, Germany; 5Institute of Physiology, Medical Faculty, Technische Universität Dresden, Dresden, Germany; 6Developmental Biology Section, Biomedical Research Foundation of the Academy of Athens, Athens, Greece; 7Institute of Immunology, Technische Universität Dresden, Dresden, Germany; 8Department of Radioimmunology, Helmholtz Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany; 9Institute of Pathology, Technische Universität Dresden, Dresden, Germany; 10Bioceros BV, Utrecht, The Netherlands; 11Division of Endocrinology, Children's Hospital, Boston, MA; 12Department of Medical Biochemistry, Subdivision Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 13Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians University, Munich, Germany.

Received 19 November 2013; accepted 19 May 2014

Published online 21 August 2014.

Address reprint requests to: Antonios Chatzigeorgiou, M.D., Ph.D., and Triantafyllos Chavakis, M.D., Department of Clinical Pathobiochemistry, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany. E-mail:[email protected] and [email protected]; fax: +49 351 458–6324.

These authors made an equal contribution.

Potential conflict of interest: Nothing to report.

This work was supported by grants from the Deutsche Forschungsgemeinschaft (CH279/5–1 [to T.C.] and SFB-1054-B08 [to E.L.]), a European Research Council Grant (no.: 281296; to T.C.), the German Center for Diabetes Research (to T.C.), and the Netherlands Organization for Scientific Research (NWO, VICI grant to E.L.).

Abstract

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. Antibody-blockade 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 obesity-related metabolic dysregulation and, especially, NASH. (Hepatology 2014;60:1196–1210)

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