ANXA1-FPR1 signaling in myeloid cells drives MASH by elevating S100A4/A11.

Inflammation plays a central role in the development of metabolic dysfunction-associated steatohepatitis (MASH). Formyl peptide receptor 1 (FPR1) in myeloid cells emerges as a crucial factor associated with the inflammatory response; however, whether and how FPR1 signaling affects MASH development remain largely unknown. Neutrophil-specific Fpr1 knockout mice and macrophage-specific Fpr1 knockout mice were generated, and subjected to high-fat high-cholesterol (HFHC, n = 6-10) or choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD, n = 5-9) feeding. After MASH diet feeding, both neutrophil and macrophage-specific Fpr1 knockout mice had lower inflammatory cell infiltration and less degree of liver fibrosis than control mice (p <0.05-0.001). Administration of a selective inhibitor of FPR1, Cyclosporin H, robustly ameliorated mouse MASH in vivo and the 3D NAC-organ human MASH model in vitro (reduction in fibrosis area by 50%, p <0.001). Mechanistically, transcriptomic analysis revealed that Fpr1 deficiency in myeloid cells limited inflammatory cell chemotaxis and migration, which were closely related with the downregulation of S100a4 and S100a11. Moreover, neutrophil-derived annexin A1 (ANXA1) activated FPR1 signaling in neutrophils and macro phages during MASH, resulting in upregulation of pro-inflammatory S100A4 and S100A11 (p <0.05-0.01). Importantly, hepatic and serum levels of ANXA1, S100A4, and S100A11 were significantly elevated in patients with MASH (n = 15 for serum samples or 20 for liver samples), which positively correlated with the hepatic levels of several pro-inflammatory genes and fibrogenic genes (p <0.05). The ANXA1-FPR1 axis in myeloid cells worsens MASH by elevating S100A4 and S100A11 levels, suggesting that pharmacological inhibition of FPR1 signaling is a promising strategy to ameliorate MASH. FPR1 in myeloid cells is a crucial factor associated with the inflammatory response; however, whether FPR1 signaling affects MASH development remains largely unknown. In this study, we demonstrated that Fpr1 deficiency in myeloid cells and administration of an FPR1 inhibitor robustly limit MASH-related fibrosis, which is closely related with the downregulation of pro-inflammatory S100A4 and S100A11. In addition, neutrophil-derived ANXA1 elevates the expression of S100A4 and S100A11 in neutrophils and macrophages by activating FPR1 signaling, suggesting that the ANXA1-FPR1-S100A4/A11 axis plays an important role in worsening MASH.