ANGPTL3 in podocytes contributes to pathogenesis of lupus nephritis by activating MSR1 in macrophage

Lupus nephritis (LN), a severe complication of systemic lupus erythematosus (SLE), is driven by immune complex deposition and inflammatory renal injury. This study uncovers a novel mechanism in which podocyte-derived angiopoietin-like protein 3 (ANGPTL3) exacerbates LN pathogenesis through macrophage scavenger receptor 1 (MSR1)-mediated activation. Protein interaction screening revealed direct binding between ANGPTL3 and MSR1, a macrophage-enriched receptor. Clinical analyses demonstrated elevated glomerular expression of ANGPTL3 and MSR1 in LN patients, correlating with reduced renal function and histopathological damage. In vitro, ANGPTL3-overexpressing podocytes activated macrophages in an MSR1-dependent manner. RNA sequencing of ANGPTL3-stimulated bone marrow-derived macrophages (BMDMs) identified robust activation of interferon signaling pathways, with key genes (Tnip3, Isg20). Silencing Msr1 abolished these effects, suppressing interferon-related gene expression. In the pristane-induced lupus model, ANGPTL3 and MSR1 co-localized with infiltrating macrophages in injured glomeruli, mirroring human LN pathology. These findings establish the ANGPTL3-MSRI axis as a critical driver of macrophage activation and interferon signaling in LN, highlighting ANGPTL3 as a promising therapeutic target to mitigate immune-mediated renal injury in SLE.