IL-21 signaling drives M1 polarization and lipid metabolic reprogramming of macrophages to promote hepatocyte injury in autoimmune hepatitis (PRJCA049633)
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease with complex pathogenesis and limited treatment options. While IL-21 signaling is known to contribute to AIH immunopathology, its specific impact on hepatic macrophages remains unclear. This study identified a distinct monocyte-derived macrophage subset characterized by high expression of IL-21 receptor (IL-21R) and significant lipid accumulation (IL-21RhiLDhi) in an experimentally established AIH mouse model. These IL-21RhiLDhi macrophages exhibited a pro-inflammatory M1-like phenotype, with upregulated expression of MHC II, CD86, and inflammatory cytokines (IL-1ß, IL-6, TNF-a). Transcriptomic profiling revealed profound fatty acid metabolic reprogramming in this subset, involving concurrent activation of both synthesis and ß-oxidation pathways. Functionally, IL-21RhiLDhi macrophages directly exacerbated hepatocyte injury in co-culture by inducing apoptosis, causing G2/M cell cycle arrest, and inhibiting proliferation. Therapeutic blockade of IL-21R signaling with a neutralizing antibody significantly ameliorated experimental AIH, improving liver function, reducing autoantibody titers, and suppressing inflammation. Crucially, macrophage depletion abrogated these therapeutic benefits, demonstrating that the efficacy of anti-IL-21R treatment is predominantly mediated through its action on macrophages. Our findings unveil a novel pathogenic IL-21RhiLDhi macrophage subset in AIH and establish the IL-21/IL-21R axis on macrophages as a promising therapeutic target for this disease.