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. Here, we found that the hepatic Treg proportion and β-catenin expression in hepatic macrophages were associated with acetaminophen- and d-galactosamine/LPS-induced acute liver injury. Interestingly, β-catenin was markedly 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 coculture experiments revealed that macrophage β-catenin modulated its exosome composition and influenced Treg differentiation. Using mass spectrometry-based proteomics, we identified that macrophage β-catenin activation increased the level of exosomal alpha soluble NSF attachment protein (α-SNAP), which in turn promoted Treg differentiation. Overall, our findings demonstrated a molecular mechanism that macrophage β-catenin regulated the Treg proportion in the liver by enhancing the expression of exosomal α-SNAP, providing insights into the pathophysiology of acute liver injury.