The fundamental mechanism how heterogeneous hepatic macrophage (MÏ †) subsets fulfill diverse functions in health and disease has not been elucidated. We recently reported that CCR9 + inflammatory M†s play a critical role in the course of acute liver injury. To clarify the origin and differentiation of CCR9 + M†s, we used a unique partial bone marrow (BM) chimera model with liver shielding for maintaining hepatic resident M †s. First, irradiated mice developed less liver injury with less M†s accumulation by Concanavalin A (Con A) regardless of liver shielding. In mice receiving further BM transplantation, CD11blowF4/80high hepatic-resident M†s were not replaced by transplanted donors under steady state, while under inflammatory state by Con A, CCR9 + M†s were firmly replaced by donors, indicating that CCR9 + M†s originate from BM, but not from hepatic-resident cells. Regarding the mechanism of differentiation and proliferation, EdU + CCR9 + M†s with a proliferative potential were detected specifically in the inflamed liver, and in vitro study revealed that BM-derived CD11b + cells co-cultured with hepatic stellate cells (HSCs) or stimulated with retinoic acids could acquire CCR9 with antigen-presenting ability. Collectively, our study demonstrates that inflammatory M†s originate from BM and became locally differentiated and proliferated by interaction with HSCs via CCR9 axis during acute liver injury.
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