ANGPTL3 in Podocytes Contributes to the Pathogenesis of Lupus Nephritis by Activating MSR1 in Macrophages.

INTRODUCTION: Lupus nephritis (LN), a severe complication of systemic lupus erythematosus (SLE), is characterized by persistent immune dysregulation and glomerular injury predominantly driven by macrophage infiltration and type I interferon (IFN-I) signaling. Crosstalk between injured podocytes and infiltrating macrophages is increasingly recognized as a key contributor to LN progression; however, the molecular mediators and their corresponding receptors remain poorly defined. This study investigates whether ANGPTL3 upregulation in podocytes activates macrophages through MSR1 and drives interferon-biased inflammation in LN.

METHODS: We employed secretome-based protein-protein interaction screening to identify ANGPTL3 receptors. The ANGPTL3-MSR1 interaction was supported by co-immunoprecipitation. In vitro, bone marrow-derived macrophages (BMDMs) were stimulated with ANGPTL3-conditioned media, and gene expression was analyzed by RNA sequencing. MSR1 was silenced using siRNA. In vivo, a pristane-induced lupus mouse model was used to assess glomerular ANGPTL3/MSR1 expression, renal function, and macrophage infiltration. Clinical relevance was assessed using Nephroseq datasets and human LN kidney specimens.

RESULTS: ANGPTL3 was identified as an MSR1-interacting ligand through a cell-based membrane protein screening assay and further supported by co-immunoprecipitation. In vitro, ANGPTL3-conditioned media induced an interferon-dominant transcriptional response in BMDMs, including upregulation of Tnip3 and Isg20. These effects were attenuated upon MSR1 silencing, confirming receptor-dependent activation. Notably, ANGPTL3 had minimal effect on M1/M2 polarization markers, indicating selective regulation of interferon signaling. Analysis of Nephroseq datasets and LN biopsies demonstrated elevated ANGPTL3 and MSR1 expression, which correlated with histopathological severity. Single-cell RNA-seq confirmed MSR1 enrichment in glomerular macrophages. In vivo, pristane-induced lupus mice exhibited increased glomerular ANGPTL3, Synaptopodin loss, proteinuria, and colocalization of F4/80 and MSR1, supporting a pathogenic podocyte-macrophage axis.

CONCLUSION: This study identifies the ANGPTL3-MSR1 axis as a critical pathway linking podocyte injury to macrophage-driven inflammation in LN, highlighting its therapeutic potential. Targeting this axis may disrupt maladaptive immune crosstalk, offering a novel strategy for LN management.