TY - JOUR
T1 - CD11c+ resident macrophages drive hepatocyte death-triggered liver fibrosis in a murine model of nonalcoholic steatohepatitis
AU - Itoh, Michiko
AU - Suganami, Takayoshi
AU - Kato, Hideaki
AU - Kanai, Sayaka
AU - Shirakawa, Ibuki
AU - Sakai, Takeru
AU - Goto, Toshihiro
AU - Asakawa, Masahiro
AU - Hidaka, Isao
AU - Sakugawa, Hiroshi
AU - Ohnishi, Koji
AU - Komohara, Yoshihiro
AU - Asano, Kenichi
AU - Sakaida, Isao
AU - Tanaka, Masato
AU - Ogawa, Yoshihiro
N1 - Funding Information:
The authors thank Joel K. Elmquist for the gift of MC4R-KO mice, Steffen Jung and Toshiaki Ohteki for CD11c-DTR-transgenic mice, and Miyako Tanaka (Nagoya University) for support of microarray analysis. We also thank the members of the Ogawa laboratory for helpful discussions. This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (16H05171, 16KT0110, 16K08732, 17K19686, and 17H05500) and Japan Agency for Medical Research and Development (CREST). This work was also supported by research grants from the Takeda Science Foundation, the Takeda Medical Research Foundation, the Uehara Memorial Foundation, the Suzuken Memorial Foundation, the Daiichi Sankyo Foundation of Life Science, the Japan Diabetes Society, and the Joint Usage/Research Program of Medical Research Institute, Tokyo Medical and Dental University.
Publisher Copyright:
© 2017 JCI Insight. All rights reserved.
PY - 2017/11/16
Y1 - 2017/11/16
N2 - 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.
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.
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M3 - Article
C2 - 29202448
AN - SCOPUS:85046423533
VL - 2
JO - JCI insight
JF - JCI insight
SN - 2379-3708
IS - 22
M1 - e92902
ER -