CCR9⁺ macrophages are required for 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 ⁺SiglecH⁺CD11bCD11c^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 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⁺CD16^high monocytes than controls. Conclusions: CCR9⁺ macrophages contribute to the induction of acute liver inflammation in mouse models of hepatitis.