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Published on: August 12, 2019
Bone marrow-derived CD169+ macrophages promote autoimmune hepatitis by recruiting CCR2+ monocytes via secreting CCL12
Bingru Lin1, Huayang Zhang2, Pengwei Zhu3
1Department of Gastroenterology, Zhejiang Provincial Clinical Research Center for Digestive Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Abstract:
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 Ly6ChiCD169+ 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.
Insights
CD169-positive macrophages drive autoimmune hepatitis by secreting CCL12, recruiting more immune cells. Depleting these macrophages or neutralizing CCL12 improves liver injury and immune balance in AIH.
Area of Science:
- Immunology
- Hepatology
- Autoimmune Diseases
Background:
- CD169+ macrophages are linked to autoimmune diseases, but their role in autoimmune hepatitis (AIH) is unclear.
- This study investigates the specific function and therapeutic potential of CD169+ macrophages in AIH.
Purpose of the Study:
- To elucidate the role of CD169+ macrophages in the pathogenesis of autoimmune hepatitis (AIH).
- To identify CD169+ macrophages as a potential therapeutic target for AIH.
Main Methods:
- Analysis of liver biopsies from AIH patients and a mouse model of acute liver injury.
- Depletion of CD169+ macrophages, cytokine stimulation, chemokine secretion assays, and immune cell profiling.
- Neutralization of key chemokines involved in macrophage recruitment.
Main Results:
- Increased CD169+ macrophage infiltration in AIH livers correlated with inflammation.
- Depletion of CD169+ macrophages ameliorated ConA-induced liver injury and improved immune homeostasis.
- Bone marrow-derived Ly6ChiCD169+ macrophages were identified as crucial; they secrete CCL12 in response to IFNγ, recruiting CCR2+ monocytes/macrophages.
- Neutralizing CCL12 significantly improved AIH.
Conclusions:
- Bone marrow-derived CD169+ macrophages exacerbate AIH by secreting CCL12, driven by IFNγ signaling.
- These macrophages recruit CCR2+ monocytes and macrophages, worsening liver inflammation.
- Targeting CD169+ macrophages or CCL12 presents a promising therapeutic strategy for AIH.
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