CCR9+ Macrophages Are Required for Acute Liver Inflammation in Mouse Models of Hepatitis

Background & AimsAntigen-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.MethodsWe used concanavalin A (con A) or carbon tetrachloride to induce acute liver inflammation in mice and studied the roles of macrophages that express CCR9.ResultsAfter 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–CD11clow 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+CD16high monocytes than controls.ConclusionsCCR9+ macrophages contribute to the induction of acute liver inflammation in mouse models of hepatitis.