Kai Markus Schneider1, Veerle Bieghs1, Felix Heymann1, Wei Hu1, Daniela Dreymueller2, Lijun Liao1, Mick Frissen1, Andreas Ludwig2, Nikolaus Gassler3, Oliver Pabst4, Eicke Latz5,6,7, Gernot Sellge1, John Penders8, Frank Tacke1, Christian Trautwein1. 1. Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany. 2. Institute of Pharmacology and Toxicology, Medical Faculty, University Hospital, RWTH Aachen, Aachen, Germany. 3. Institute of Pathology, University Hospital, RWTH Aachen, Aachen, Germany. 4. Institute of Molecular Medicine, University Hospital, RWTH Aachen, Aachen, Germany. 5. Institute of Innate Immunity, University Hospital, University of Bonn, Bonn, Germany. 6. Department of Medicine, University of Massachusetts Medical School, Worcester, MA. 7. German Center for Neurodegenerative Diseases, Bonn, Germany. 8. Department of Medical Microbiology, School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands.
Abstract
UNLABELLED: Nonalcoholic fatty liver disease is seen as the hepatic manifestation of the metabolic syndrome and represents the most common liver disease in Western societies. The G protein-coupled chemokine receptor CX3CR1 plays a central role in several metabolic syndrome-related disease manifestations and is involved in maintaining intestinal homeostasis. Because diet-induced intestinal dysbiosis is a driver for nonalcoholic fatty liver disease, we hypothesized that CX3CR1 may influence the development of steatohepatitis. In two independent models of diet-induced steatohepatitis (high-fat diet and methionine/choline-deficient diet), CX3CR1 protected mice from excessive hepatic steatosis and inflammation, as well as systemic glucose intolerance. Lack of Cx3cr1 expression was associated with significantly altered intestinal microbiota composition, which was linked to an impaired intestinal barrier. Concomitantly, endotoxin levels in portal serum and inflammatory macrophages in liver were increased in Cx3cr1-/- mice, indicating an increased inflammatory response. Depletion of intestinal microbiota by administration of broad-spectrum antibiotics suppressed the number of infiltrating macrophages and promoted macrophage polarization in liver. Consequently, antibiotic-treated mice demonstrated a marked improvement of steatohepatitis. CONCLUSION: Microbiota-mediated activation of the innate immune responses through CX3CR1 is crucial for controlling steatohepatitis progression, which recognizes CX3CR1 as an essential gatekeeper in this scenario.
UNLABELLED: Nonalcoholic fatty liver disease is seen as the hepatic manifestation of the metabolic syndrome and represents the most common liver disease in Western societies. The G protein-coupled chemokine receptor CX3CR1 plays a central role in several metabolic syndrome-related disease manifestations and is involved in maintaining intestinal homeostasis. Because diet-induced intestinal dysbiosis is a driver for nonalcoholic fatty liver disease, we hypothesized that CX3CR1 may influence the development of steatohepatitis. In two independent models of diet-induced steatohepatitis (high-fat diet and methionine/choline-deficient diet), CX3CR1 protected mice from excessive hepatic steatosis and inflammation, as well as systemic glucose intolerance. Lack of Cx3cr1 expression was associated with significantly altered intestinal microbiota composition, which was linked to an impaired intestinal barrier. Concomitantly, endotoxin levels in portal serum and inflammatory macrophages in liver were increased in Cx3cr1-/- mice, indicating an increased inflammatory response. Depletion of intestinal microbiota by administration of broad-spectrum antibiotics suppressed the number of infiltrating macrophages and promoted macrophage polarization in liver. Consequently, antibiotic-treated mice demonstrated a marked improvement of steatohepatitis. CONCLUSION: Microbiota-mediated activation of the innate immune responses through CX3CR1 is crucial for controlling steatohepatitis progression, which recognizes CX3CR1 as an essential gatekeeper in this scenario.
Authors: Kai Markus Schneider; Antje Mohs; Wenfang Gui; Eric J C Galvez; Lena Susanna Candels; Lisa Hoenicke; Uthayakumar Muthukumarasamy; Christian H Holland; Carsten Elfers; Konrad Kilic; Carolin Victoria Schneider; Robert Schierwagen; Pavel Strnad; Theresa H Wirtz; Hanns-Ulrich Marschall; Eicke Latz; Benjamin Lelouvier; Julio Saez-Rodriguez; Willem de Vos; Till Strowig; Jonel Trebicka; Christian Trautwein Journal: Nat Commun Date: 2022-07-08 Impact factor: 17.694
Authors: Magar Ghazarian; Xavier S Revelo; Mark K Nøhr; Helen Luck; Kejing Zeng; Helena Lei; Sue Tsai; Stephanie A Schroer; Yoo Jin Park; Melissa Hui Yen Chng; Lei Shen; June Ann D'Angelo; Peter Horton; William C Chapman; Diane Brockmeier; Minna Woo; Edgar G Engleman; Oyedele Adeyi; Naoto Hirano; Tianru Jin; Adam J Gehring; Shawn Winer; Daniel A Winer Journal: Sci Immunol Date: 2017-04-21
Authors: R Brauer; J Tureckova; I Kanchev; M Khoylou; J Skarda; J Prochazka; F Spoutil; I M Beck; O Zbodakova; P Kasparek; V Korinek; K Chalupsky; T Karhu; K-H Herzig; M Hajduch; M Gregor; R Sedlacek Journal: Mucosal Immunol Date: 2015-11-11 Impact factor: 7.313