ANXA1-mediated mTOR/FABP4 Inhibition Drives Antifibrotic Macrophage Reprogramming in Lupus Nephritis

TL;DR

This study shows that Annexin A1 (ANXA1) helps reduce kidney fibrosis in lupus by reprogramming macrophages, suggesting a new treatment approach.

Contribution

The study identifies ANXA1's role in reprogramming macrophages via mTOR/FABP4 inhibition, offering new therapeutic targets for lupus nephritis.

Findings

ANXA1 expression is elevated in lupus nephritis patients and correlates with fibrosis severity.

ANXA1 signaling via FPR2/ALX inhibits mTOR/FABP4 activity, promoting antifibrotic macrophage polarization.

Treatment with Ac2-26 peptide reduces fibrosis and kidney injury in lupus-prone mice.

Abstract

Inflammation and fibrosis are central pathological processes in lupus nephritis (LN). Annexin A1 (ANXA1), a protein highly expressed in myeloid cells, is a key modulator of inflammation and fibrosis. In this study, we found that renal ANXA1 expression was elevated in LN patients and correlated positively with the severity of fibrosis. Single-cell RNA sequencing identified a distinct monocyte-derived Anxa1+Spp1+ macrophage subset that expands during nephritis and displays a profibrotic transcriptional signature. Mechanistically, ANXA1 signals via the FPR2/ALX receptor to inhibit mTOR/FABP4 activity in macrophages, enhance fatty acid oxidation, and thereby drive a polarization shift toward an antifibrotic phenotype. Consequently, treatment with the ANXA1-mimetic peptide Ac2-26 attenuated macrophage-driven fibrosis, reduced renal lipid accumulation, and ameliorated kidney injury in lupus-prone mice. These findings underscore the critical role of ANXA1 and Anxa1+Spp1+ macrophages in renal fibrosis progression, offering novel therapeutic targets for LN.

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