Bone marrow-derived macrophages distinct from tissue-resident macrophages play a pivotal role in Concanavalin A-induced murine liver injury via CCR9 axis.

ABSTRACT: The fundamental mechanism how heterogeneous hepatic macrophage (M?) 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, CD11b(low)F4/80(high) 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.

SUBMITTER: Amiya T 

PROVIDER: S-EPMC5057133 | biostudies-other | 2016 Oct

REPOSITORIES: biostudies-other