CD1d acts as a ligand of PIRA2 to promote macrophage activation in nonalcoholic fatty liver disease

Liver inflammation is a key driver of nonalcoholic fatty liver disease (NAFLD) and its progressive subtype, nonalcoholic steatohepatitis (NASH). Macrophages, as central players in the innate immune response, are crucial to disease pathogenesis; however, the upstream events that initiate their activation remain poorly defined. Here, we employed a cell-based chimeric receptor screening system and identified CD1d as a surface ligand for PIRA2. We subsequently demonstrated that CD1d stimulation activated macrophages both in vitro and in vivo. Using Pira2-deficient (Pira2⁻/⁻) mice, we observed significantly reduced hepatic inflammation and lipid accumulation compared to wild-type controls. Mechanistically, CD1d–PIRA2 interaction involves the α1 and α2 domains of CD1d and the D1 and D2 domains of PIRA2, leading to FcRγ ITAM tyrosine phosphorylation and downstream inflammatory signaling—events that are impaired in Pira2⁻/⁻ macrophages. Additionally, CD1d and LILRA2 protein levels were elevated in NAFLD patients, and CD1d stimulation induced proinflammatory cytokine expression in human macrophages, which was attenuated by LILRA2 blockade. A recombinant LILRA2/Fc fusion protein effectively blocked CD1d-induced inflammatory gene expression in human macrophages, highlighting its potential as a therapeutic strategy for NAFLD. Collectively, our findings identify CD1d as a functional ligand of PIRA2 that promotes macrophage activation and inflammation, contributing to NAFLD progression.