PMID- 29202448 OWN - NLM STAT- MEDLINE DCOM- 20190708 LR - 20190708 IS - 2379-3708 (Electronic) IS - 2379-3708 (Linking) VI - 2 IP - 22 DP - 2017 Nov 16 TI - CD11c+ resident macrophages drive hepatocyte death-triggered liver fibrosis in a murine model of nonalcoholic steatohepatitis. LID - 92902 [pii] LID - 10.1172/jci.insight.92902 [doi] LID - e92902 AB - Although recent evidence has pointed to the role of organ- and pathogenesis-specific macrophage subsets, it is still unclear which subsets are critically involved in the pathogenesis of nonalcoholic steatohepatitis (NASH). Using melanocortin-4 receptor-deficient (MC4R-KO) mice fed Western diet (WD), which exhibit liver phenotypes similar to those of human NASH, we found a histological structure, termed hepatic crown-like structure (hCLS), in which CD11c+ macrophages surround dead/dying hepatocytes, a prominent feature of NASH. Here, we demonstrate that hCLS-constituting macrophages could be a novel macrophage subset that drives hepatocyte death-triggered liver fibrosis. In an "inducible NASH model," hepatocyte death induces hCLS formation and liver fibrosis sequentially in the short term. In combination with the long-term WD feeding model, we also showed that resident macrophages are a major cellular source of CD11c+ macrophages constituting hCLS, which exhibited gene expression profiles distinct from CD11c- macrophages scattered in the liver. Moreover, depletion of CD11c+ macrophages abolished hCLS formation and fibrogenesis in NASH. Our clinical data suggest the role of CD11c+ macrophages in the disease progression from simple steatosis to NASH. This study sheds light on the role of resident macrophages, in addition to recruited macrophages, in the pathogenesis of NASH. FAU - Itoh, Michiko AU - Itoh M AD - Department of Organ Network and Metabolism and. FAU - Suganami, Takayoshi AU - Suganami T AD - Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. AD - Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan. FAU - Kato, Hideaki AU - Kato H AD - Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. AD - Drug Discovery & Disease Research Laboratory, Shionogi & Co. Ltd., Osaka, Japan. FAU - Kanai, Sayaka AU - Kanai S AD - Department of Molecular and Cellular Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Shirakawa, Ibuki AU - Shirakawa I AD - Department of Organ Network and Metabolism and. FAU - Sakai, Takeru AU - Sakai T AD - Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Goto, Toshihiro AU - Goto T AD - Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Asakawa, Masahiro AU - Asakawa M AD - Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. FAU - Hidaka, Isao AU - Hidaka I AD - Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan. FAU - Sakugawa, Hiroshi AU - Sakugawa H AD - Heart Life Hospital, Okinawa, Japan. FAU - Ohnishi, Koji AU - Ohnishi K AD - Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. FAU - Komohara, Yoshihiro AU - Komohara Y AD - Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. FAU - Asano, Kenichi AU - Asano K AD - Laboratory of Immune regulation, School of Life Science, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan. FAU - Sakaida, Isao AU - Sakaida I AD - Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan. FAU - Tanaka, Masato AU - Tanaka M AD - Laboratory of Immune regulation, School of Life Science, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan. FAU - Ogawa, Yoshihiro AU - Ogawa Y AD - Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. AD - Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan. AD - Department of Molecular and Cellular Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. AD - Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. AD - Japan Agency for Medical Research and Development, CREST, Tokyo, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20171116 PL - United States TA - JCI Insight JT - JCI insight JID - 101676073 RN - 0 (CD11c Antigen) RN - 0 (Ccr2 protein, mouse) RN - 0 (Receptor, Melanocortin, Type 4) RN - 0 (Receptors, CCR2) SB - IM MH - Animals MH - CD11c Antigen/immunology/*metabolism MH - Disease Models, Animal MH - Disease Progression MH - Fatty Liver/pathology MH - Hepatocytes/*metabolism/pathology MH - Humans MH - Inflammation MH - Liver/pathology MH - Liver Cirrhosis/*pathology MH - Macrophages/*immunology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Non-alcoholic Fatty Liver Disease/*pathology MH - Obesity/complications MH - Receptor, Melanocortin, Type 4/genetics MH - Receptors, CCR2 PMC - PMC5752377 OTO - NOTNLM OT - Fibrosis OT - Hepatology OT - Inflammation OT - Macrophages OT - Obesity COIS- Conflict of interest: M. Itoh and I. Shirakawa are assigned to the Joint Research Department of Tokyo Medical and Dental University and Shionogi & Co. Ltd. EDAT- 2017/12/05 06:00 MHDA- 2019/07/10 06:00 PMCR- 2017/11/16 CRDT- 2017/12/05 06:00 PHST- 2017/01/20 00:00 [received] PHST- 2017/10/17 00:00 [accepted] PHST- 2017/12/05 06:00 [pubmed] PHST- 2019/07/10 06:00 [medline] PHST- 2017/12/05 06:00 [entrez] PHST- 2017/11/16 00:00 [pmc-release] AID - 92902 [pii] AID - 10.1172/jci.insight.92902 [doi] PST - epublish SO - JCI Insight. 2017 Nov 16;2(22):e92902. doi: 10.1172/jci.insight.92902. eCollection 2017 Nov 16.