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

Area of Science:

• Nephrology
• Immunology
• Molecular Biology

Background:

• Inflammation and fibrosis are key pathological features of lupus nephritis (LN).
• Annexin A1 (ANXA1), a protein in myeloid cells, regulates inflammation and fibrosis.
• Elevated ANXA1 expression correlates with fibrosis severity in LN patients.

Purpose of the Study:

• To investigate the role of ANXA1 and specific macrophage subsets in renal fibrosis in lupus nephritis.
• To explore ANXA1 signaling pathways in macrophages and their impact on fibrosis.
• To evaluate the therapeutic potential of ANXA1-based interventions in a mouse model of LN.

Main Methods:

• Analysis of ANXA1 expression in LN patients.
• Single-cell RNA sequencing to identify macrophage subsets.
• Mechanistic studies on ANXA1 signaling via FPR2/ALX receptor.
• Treatment of lupus-prone mice with ANXA1-mimetic peptide Ac2-26.

Main Results:

• Renal ANXA1 expression was elevated in LN patients and correlated with fibrosis.
• A novel monocyte-derived Anxa1⁺Spp1⁺ macrophage subset with profibrotic signature was identified.
• ANXA1 signaling promoted an antifibrotic macrophage phenotype by enhancing fatty acid oxidation.
• Ac2-26 treatment reduced macrophage-driven fibrosis, renal lipid accumulation, and kidney injury in mice.

Conclusions:

• ANXA1 and Anxa1⁺Spp1⁺ macrophages are critical in driving renal fibrosis in LN.
• Targeting ANXA1 signaling presents a promising therapeutic strategy for lupus nephritis.