FGL1 modulates macrophage function and enhances liver repair through LAG3-TNFR1 axis.

Abstract

Fibrinogen-like protein 1 (FGL1), a liver-derived secretory factor, functions as a major histocompatibility complex class II (MHC-II)-independent ligand for lymphocyte activation gene 3 (LAG3), potentially offering protection against liver damage. However, the precise immunomodulatory mechanisms of FGL1 in liver repair remain largely undefined. This study aims to elucidate the role and underlying mechanisms of FGL1 in modulating macrophage function and promoting liver injury resolution. Using both acute liver injury (ALI) mouse models and bone marrow-derived macrophages (BMDMs), we examined the effects of FGL1 on macrophage function. Our findings suggest that FGL1 effectively attenuates the production of pro-inflammatory cytokines, thereby mitigating liver inflammation. Mechanistically, FGL1 binding to LAG3 leads to the downregulation of tumor necrosis factor receptor 1 (TNFR1) expression and subsequent suppression of NF-κB signaling. These molecular events promote M2 macrophage polarization while inhibiting M1 activation, enhancing the regenerative potential of injured livers. This study provides novel insights into the therapeutic potential of FGL1 in inflammatory liver disorders by modulating macrophage function and promoting liver repair. These results highlight its potential as a novel anti-inflammatory therapeutic agent for the treatment of inflammatory liver diseases.