β-catenin disruption decreases macrophage exosomal α-SNAP and impedes Treg differentiation in acute liver injury

Hepatic macrophages and regulatory T cells (Tregs) play an important role in the maintenance of liver immune homeostasis, but the mechanism by which hepatic macrophages regulate Tregs in acute liver injury remains largely unknown.We found that the hepatic Treg proportion and β-catenin expression in hepatic macrophages were associated with APAP and D-GalN/LPS-induced acute liver injury. Interestingly, β-catenin was significantly upregulated only in infiltrating macrophages, but not in resident Kupffer cells. Myeloid-specific β-catenin knockout mice showed an increased inflammatory cell infiltration and hepatocyte apoptosis. Moreover, myeloid β-catenin deficiency decreased the hepatic Treg proportion in the injured liver. Mechanistically, in vitro co-culture experiments revealed that macrophage β-catenin modulated its exosome composition, and influenced Tregs differentiation. Using mass spectrometry-based proteomics, we identified that macrophage β-catenin disruption decreased the level of exosomal α-SNAP, which in turn prevents Treg differentiation.