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

Area of Science:

• Hepatology and Immunology
• Molecular Biology

Background:

• Inflammation is central to metabolic dysfunction-associated steatohepatitis (MASH) development.
• Formyl peptide receptor 1 (FPR1) in myeloid cells is implicated in inflammation, but its role in MASH is unclear.

Purpose of the Study:

• To investigate the role of FPR1 signaling in myeloid cells in MASH pathogenesis.
• To explore the therapeutic potential of FPR1 inhibition for MASH.

Main Methods:

• Generated neutrophil- and macrophage-specific Fpr1 knockout mice.
• Administered high-fat, high-cholesterol (HFHC) or choline-deficient, L-amino acid-defined, high-fat diets (CDAHFD).
• Utilized a selective FPR1 inhibitor (Cyclosporin H) in mouse and human MASH models.

Main Results:

• Fpr1 deficiency in myeloid cells reduced inflammatory cell infiltration and liver fibrosis in MASH models.
• FPR1 inhibition ameliorated MASH in vivo and in a human MASH organoid model.
• Transcriptomic analysis revealed Fpr1 deficiency downregulated S100a4 and S100a11, limiting myeloid cell migration.
• Neutrophil-derived annexin A1 (ANXA1) activated FPR1, upregulating S100A4 and S100A11.
• Elevated ANXA1, S100A4, and S100A11 levels in MASH patients correlated with proinflammatory and fibrogenic gene expression.

Conclusions:

• The ANXA1-FPR1 axis in myeloid cells exacerbates MASH by increasing S100A4 and S100A11.
• Pharmacological inhibition of FPR1 signaling is a potential therapeutic strategy for MASH.