Bone marrow-derived CD169macrophages promote autoimmune hepatitis by recruiting CCR2monocytes via secreting CCL12.

Abstract

CD169macrophages, a unique subset of macrophages that cannot be simply defined as M1 or M2 macrophages, have been reported to be associated with various autoimmune diseases. However, the role of CD169macrophages in autoimmune hepatitis (AIH) is largely unknown. Here we found that the infiltration of CD169macrophages increased in the liver of patients with AIH and strongly positively correlated with inflammation degree. In a mouse model, depletion of CD169macrophages ameliorated ConA-induced acute liver injury. Immune homeostasis was also improved when CD169macrophages were depleted, as the infiltration of monocytes, macrophages and T cells decreased. Bone marrow-derived Ly6CCD169macrophages were further identified as the crucial subset in AIH. Next, we found that CD169macrophages were IFNγ-responsive and IFNγ could induce the expression of CD169. In response to the IFNγ signal, CD169macrophages actively secrete chemokine (C-C motif) ligand (CCL12), thus recruiting CCR2monocytes and macrophages to exacerbate AIH. Finally, neutralizing CCL12 improved AIH. Our results suggest that bone marrow-derived CD169macrophages, the key subset of macrophages in AIH, actively secrete CCL12 in response to IFNγ to recruit CCR2monocytes and macrophages, thus exacerbating AIH. The CD169macrophages are a potential therapeutic target in AIH.