<p>CD169⁺ macrophages, 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 CD169⁺ macrophages in autoimmune hepatitis (AIH) is largely unknown. Here we found that the infiltration of CD169⁺ macrophages increased in the liver of patients with AIH and strongly positively correlated with inflammation degree. In a mouse model, depletion of CD169⁺ macrophages ameliorated ConA-induced acute liver injury. Immune homeostasis was also improved when CD169⁺ macrophages were depleted, as the infiltration of monocytes, macrophages and T cells decreased. Bone marrow-derived Ly6C^hiCD169⁺ macrophages were further identified as the crucial subset in AIH. Next, we found that CD169⁺ macrophages were IFNγ-responsive and IFNγ could induce the expression of CD169. In response to the IFNγ signal, CD169⁺ macrophages actively secrete chemokine (C–C motif) ligand (CCL12), thus recruiting CCR2⁺ monocytes and macrophages to exacerbate AIH. Finally, neutralizing CCL12 improved AIH. Our results suggest that bone marrow-derived CD169⁺ macrophages, the key subset of macrophages in AIH, actively secrete CCL12 in response to IFNγ to recruit CCR2⁺ monocytes and macrophages, thus exacerbating AIH. The CD169⁺ macrophages are a potential therapeutic target in AIH.</p><p></p>