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⁺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.

Keywords:  Immune Regulation , Hepatic Disease , Chemokine Receptor , T-Cell Activation

Abbreviations used in this paper:  AH, acute hepatitis , APC, antigen-presenting cell , CH, chronic hepatitis , cDC, conventional dendritic cell , con A, concanavalin A , GAPDH, glyceraldehyde-3-phosphate dehydrogenase , IFN, interferon , IL, interleukin , mAb, monoclonal antibody , NC, normal control , NKT, natural killer T , PB, peripheral blood , pDC, plasmacytoid dendritic cell , TLR, Toll-like receptor , TNF, tumor necrosis factor , WT, wild-type