BACKGROUND & AIMS: Antigen-presenting cells (APCs) are involved in the induction of liver inflammation. We investigated the roles of specific APCs in the pathogenesis of acute liver injury in mice. METHODS: We used concanavalin A (con A) or carbon tetrachloride to induce acute liver inflammation in mice and studied the roles of macrophages that express CCR9. RESULTS: After injection of con A, we detected CCR9(+)CD11b(+)CD11c(-) macrophages that express tumor necrosis factor (TNF)-α in livers of mice, whereas CCR9(+)Siglec-H(+)CD11b(-)CD11c(low) plasmacytoid DCs (pDCs), which are abundant in normal livers, disappeared. The CCR9(+) macrophages were also detected in the livers of RAG-2(-/-) mice, which lack lymphocytes and natural killer T cells, after injection of con A. Under inflammatory conditions, CCR9(+) macrophages induced naive CD4(+) T cells to become interferon gamma-producing Th1 cells in vivo and in vitro. CCR9(-/-) mice injected with con A did not develop hepatitis unless they also received CCR9(+) macrophages from mice that received con A; more CCR9(+) macrophages accumulated in their inflamed livers than CCR9(+) pDCs, CCR9(-) pDCs, or CCR9(-) macrophages isolated from mice that had received injections of con A. Levels of CCL25 messenger RNA increased in livers after injection of con A; neutralizing antibodies against CCL25 reduced the induction of hepatitis by con A by blocking the migration of CCR9(+) macrophages and their production of TNF-α. Peripheral blood samples from patients with acute hepatitis had greater numbers of TNF-α-producing CCR9(+)CD14(+)CD16(high) monocytes than controls. CONCLUSIONS: CCR9(+) macrophages contribute to the induction of acute liver inflammation in mouse models of hepatitis.
BACKGROUND & AIMS: Antigen-presenting cells (APCs) are involved in the induction of liver inflammation. We investigated the roles of specific APCs in the pathogenesis of acute liver injury in mice. METHODS: We used concanavalin A (con A) or carbon tetrachloride to induce acute liver inflammation in mice and studied the roles of macrophages that express CCR9. RESULTS: After injection of con A, we detected CCR9(+)CD11b(+)CD11c(-) macrophages that express tumor necrosis factor (TNF)-α in livers of mice, whereas CCR9(+)Siglec-H(+)CD11b(-)CD11c(low) plasmacytoid DCs (pDCs), which are abundant in normal livers, disappeared. The CCR9(+) macrophages were also detected in the livers of RAG-2(-/-) mice, which lack lymphocytes and natural killer T cells, after injection of con A. Under inflammatory conditions, CCR9(+) macrophages induced naive CD4(+) T cells to become interferon gamma-producing Th1 cells in vivo and in vitro. CCR9(-/-) mice injected with con A did not develop hepatitis unless they also received CCR9(+) macrophages from mice that received con A; more CCR9(+) macrophages accumulated in their inflamed livers than CCR9(+) pDCs, CCR9(-) pDCs, or CCR9(-) macrophages isolated from mice that had received injections of con A. Levels of CCL25 messenger RNA increased in livers after injection of con A; neutralizing antibodies against CCL25 reduced the induction of hepatitis by con A by blocking the migration of CCR9(+) macrophages and their production of TNF-α. Peripheral blood samples from patients with acute hepatitis had greater numbers of TNF-α-producing CCR9(+)CD14(+)CD16(high) monocytes than controls. CONCLUSIONS:CCR9(+) macrophages contribute to the induction of acute liver inflammation in mouse models of hepatitis.
Authors: Nicolas Jacquelot; David P Enot; Caroline Flament; Nadège Vimond; Carolin Blattner; Jonathan M Pitt; Takahiro Yamazaki; María Paula Roberti; Romain Daillère; Marie Vétizou; Vichnou Poirier-Colame; Michaëla Semeraro; Anne Caignard; Craig L Slingluff; Federica Sallusto; Sylvie Rusakiewicz; Benjamin Weide; Aurélien Marabelle; Holbrook Kohrt; Stéphane Dalle; Andréa Cavalcanti; Guido Kroemer; Anna Maria Di Giacomo; Michele Maio; Phillip Wong; Jianda Yuan; Jedd Wolchok; Viktor Umansky; Alexander Eggermont; Laurence Zitvogel Journal: J Clin Invest Date: 2016-02-08 Impact factor: 14.808
Authors: Dowty Movita; Martijn D B van de Garde; Paula Biesta; Kim Kreefft; Bart Haagmans; Elina Zuniga; Florence Herschke; Sandra De Jonghe; Harry L A Janssen; Lucio Gama; Andre Boonstra; Thomas Vanwolleghem Journal: J Virol Date: 2015-02-11 Impact factor: 5.103
Authors: Christina D Steel; Kimberly Breving; Susan Tavakoli; Woong-Ki Kim; Larry D Sanford; Richard P Ciavarra Journal: J Neuroimmunol Date: 2013-12-11 Impact factor: 3.478
Authors: Marc-André Wurbel; Severine Le Bras; Mouna Ibourk; Michael Pardo; Maria G McIntire; Dominique Coco; Raif S Geha; Edda Fiebiger; Scott B Snapper Journal: Inflamm Bowel Dis Date: 2014-07 Impact factor: 5.325