CCR9+ macrophages are required for acute liver inflammation in mouse models of hepatitis

Abstract

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 +SiglecH+CD11bCD11clow 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 gammaproducing 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-αproducing CCR9+CD14+CD16high monocytes than controls. Conclusions: CCR9+ macrophages contribute to the induction of acute liver inflammation in mouse models of hepatitis. © 2012 AGA Institute.