title: Bone marrow-derived macrophages distinct from tissue-resident macrophages play a pivotal role in Concanavalin A-induced murine liver injury via CCR9 axis.
abstract: The fundamental mechanism how heterogeneous hepatic macrophage (Mφ) subsets fulfill diverse functions in health and disease has not been elucidated. We recently reported that CCR9+inflammatory Mφs play a critical role in the course of acute liver injury. To clarify the origin and differentiation of CCR9+Mφs, we used a unique partial bone marrow (BM) chimera model with liver shielding for maintaining hepatic resident Mφs. First, irradiated mice developed less liver injury with less Mφs accumulation by Concanavalin A (Con A) regardless of liver shielding. In mice receiving further BM transplantation, CD11blowF4/80highhepatic-resident Mφs were not replaced by transplanted donors under steady state, while under inflammatory state by Con A, CCR9+Mφs were firmly replaced by donors, indicating that CCR9+Mφs originate from BM, but not from hepatic-resident cells. Regarding the mechanism of differentiation and proliferation, EdU+CCR9+Mφs with a proliferative potential were detected specifically in the inflamed liver, and in vitro study revealed that BM-derived CD11b+cells co-cultured with hepatic stellate cells (HSCs) or stimulated with retinoic acids could acquire CCR9 with antigen-presenting ability. Collectively, our study demonstrates that inflammatory Mφs originate from BM and became locally differentiated and proliferated by interaction with HSCs via CCR9 axis during acute liver injury.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.|Research Unit/Frontier Therapeutic Sciences, Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan.
authors.forename: Takeru
authors.initials: T
authors.lastname: Amiya
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nakamoto
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Po-Sung
authors.initials: PS
authors.lastname: Chu
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Teratani
authors.affiliation: Department of Stem Cell and ImmuneRegulation, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nakajima
authors.affiliation: Department of Pathophysiology, Faculty of Pharmaceutical Sciences, Hoshi University, Tokyo, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Fukuchi
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Taniki
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yamaguchi
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Shiba
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Rei
authors.initials: R
authors.lastname: Miyake
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Katayama
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Ebinuma
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanai
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000032:analysis; D002454:Cell Differentiation; D049109:Cell Proliferation; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D003208:Concanavalin A / Q000008:administration & dosage / Q000378:metabolism*; D007155:Immunologic Factors / Q000008:administration & dosage / Q000378:metabolism*; D008099:Liver / Q000473:pathology; D008264:Macrophages / Q000737:chemistry / Q000145:classification / Q000276:immunology*; D051379:Mice; D054388:Receptors, CCR / Q000032:analysis
chemical_list: C119309:CC chemokine receptor 9; D039481:CD11b Antigen; D007155:Immunologic Factors; D054388:Receptors, CCR; D003208:Concanavalin A