PMID- 36362037 OWN - NLM STAT- MEDLINE DCOM- 20221128 LR - 20221128 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 23 IP - 21 DP - 2022 Oct 31 TI - Roles of Macrophages in Advanced Liver Fibrosis, Identified Using a Newly Established Mouse Model of Diet-Induced Non-Alcoholic Steatohepatitis. LID - 10.3390/ijms232113251 [doi] LID - 13251 AB - Macrophages play critical roles in the pathogenesis of non-alcoholic steatohepatitis (NASH). However, it is unclear which macrophage subsets are critically involved in the development of inflammation and fibrosis in NASH. In TSNO mice fed a high-fat/cholesterol/cholate-based diet, which exhibit advanced liver fibrosis that mimics human NASH, we found that Kupffer cells (KCs) were less abundant and recruited macrophages were more abundant, forming hepatic crown-like structures (hCLS) in the liver. The recruited macrophages comprised two subsets: CD11c(+)/Ly6C(-) and CD11c(-)/Ly6C(+) cells. CD11c(+) cells were present in a mesh-like pattern around the lipid droplets, constituting the hCLS. In addition, CD11c(+) cells colocalized with collagen fibers, suggesting that this subset of recruited macrophages might promote advanced liver fibrosis. In contrast, Ly6C(+) cells were present in doughnut-like inflammatory lesions, with a lipid droplet in the center. Finally, RNA sequence analysis indicates that CD11c(+)/Ly6C(-) cells promote liver fibrosis and hepatic stellate cell (HSC) activation, whereas CD11c(-)/Ly6C(+) cells are a macrophage subset that play an anti-inflammatory role and promote tissue repair in NASH. Taken together, our data revealed changes in liver macrophage subsets during the development of NASH and shed light on the roles of the recruited macrophages in the pathogenesis of advanced fibrosis in NASH. FAU - Tada, Yuki AU - Tada Y AD - Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Toyama 939-0398, Japan. FAU - Kasai, Kaichi AU - Kasai K AD - Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Toyama 939-0398, Japan. FAU - Makiuchi, Nana AU - Makiuchi N AD - Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Toyama 939-0398, Japan. FAU - Igarashi, Naoya AU - Igarashi N AD - Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Toyama 939-0398, Japan. FAU - Kani, Koudai AU - Kani K AD - Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Toyama 939-0398, Japan. FAU - Takano, Shun AU - Takano S AD - Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Toyama 939-0398, Japan. FAU - Honda, Hiroe AU - Honda H AD - Toyama Prefectural Institute for Pharmaceutical Research, 17-1 Nakataikouyama, Toyama 939-0363, Japan. FAU - Yanagibashi, Tsutomu AU - Yanagibashi T AD - Toyama Prefectural Institute for Pharmaceutical Research, 17-1 Nakataikouyama, Toyama 939-0363, Japan. FAU - Watanabe, Yasuharu AU - Watanabe Y AD - Toyama Prefectural Institute for Pharmaceutical Research, 17-1 Nakataikouyama, Toyama 939-0363, Japan. FAU - Usui-Kawanishi, Fumitake AU - Usui-Kawanishi F AD - Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Toyama 939-0398, Japan. FAU - Furusawa, Yukihiro AU - Furusawa Y AD - Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Toyama 939-0398, Japan. FAU - Ichimura-Shimizu, Mayuko AU - Ichimura-Shimizu M AUID- ORCID: 0000-0003-4030-1249 AD - Department of Pathology and Laboratory Medicine, Tokushima University Graduate School of Biomedical Sciences, 3-8-15 Kuramoto-cho, Tokushima 770-8503, Japan. FAU - Tabuchi, Yoshiaki AU - Tabuchi Y AD - Division of Molecular Genetics Research, Life Science Research Center, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. FAU - Takatsu, Kiyoshi AU - Takatsu K AD - Toyama Prefectural Institute for Pharmaceutical Research, 17-1 Nakataikouyama, Toyama 939-0363, Japan. FAU - Tsuneyama, Koichi AU - Tsuneyama K AUID- ORCID: 0000-0002-0670-9868 AD - Department of Pathology and Laboratory Medicine, Tokushima University Graduate School of Biomedical Sciences, 3-8-15 Kuramoto-cho, Tokushima 770-8503, Japan. FAU - Nagai, Yoshinori AU - Nagai Y AD - Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Toyama 939-0398, Japan. LA - eng GR - JP22K07005/Japan Society for the Promotion of Science/ GR - N.A./The Toyama Pharmaceutical Valley Development Consortium/ PT - Journal Article DEP - 20221031 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (CD11c Antigen) SB - IM MH - Animals MH - Mice MH - CD11c Antigen MH - Diet, High-Fat/adverse effects MH - Disease Models, Animal MH - Fibrosis MH - Liver/pathology MH - Liver Cirrhosis/etiology/pathology MH - *Macrophages/metabolism/pathology MH - Mice, Inbred C57BL MH - *Non-alcoholic Fatty Liver Disease/etiology/pathology PMC - PMC9654696 OTO - NOTNLM OT - Kupffer cell OT - fibrosis OT - inflammation OT - macrophage OT - non-alcoholic fatty liver disease OT - non-alcoholic steatohepatitis COIS- The authors declare no conflict of interest. EDAT- 2022/11/12 06:00 MHDA- 2022/11/15 06:00 PMCR- 2022/10/31 CRDT- 2022/11/11 01:27 PHST- 2022/10/07 00:00 [received] PHST- 2022/10/26 00:00 [revised] PHST- 2022/10/29 00:00 [accepted] PHST- 2022/11/11 01:27 [entrez] PHST- 2022/11/12 06:00 [pubmed] PHST- 2022/11/15 06:00 [medline] PHST- 2022/10/31 00:00 [pmc-release] AID - ijms232113251 [pii] AID - ijms-23-13251 [pii] AID - 10.3390/ijms232113251 [doi] PST - epublish SO - Int J Mol Sci. 2022 Oct 31;23(21):13251. doi: 10.3390/ijms232113251.