Lupus nephritis (LN) is a severe and heterogeneous complication of systemic lupus erythematosus (SLE) and remains a major cause of chronic kidney disease and end-stage renal failure despite advances in immunosuppressive and biologic therapies. LN is characterized by sustained immune dysregulation, immune-complex–associated glomerular inflammation, and progressive loss of glomerular filtration barrier integrity. Among infiltrating immune cells, macrophages have emerged as central drivers of renal injury through cytokine production, oxidative stress, and amplification of tissue inflammation. In parallel, type I interferon (IFN-I) signaling represents a hallmark pathway in SLE pathogenesis and correlates with disease activity and tissue damage across multiple organs, including the kidney. Podocytes, which are essential for maintaining the glomerular filtration barrier, are increasingly recognized not only as passive victims of inflammation but also as active participants in the renal immune microenvironment. Crosstalk between injured podocytes and infiltrating macrophages is increasingly viewed as a key contributor to LN progression; however, the molecular mediators released by podocytes and their corresponding receptors on macrophages remain incompletely defined. Angiopoietin-like protein 3 (ANGPTL3) is a secreted glycoprotein implicated in metabolic regulation and tissue injury. While ANGPTL3 has been linked to podocyte dysfunction in other kidney disease contexts, its role in LN-associated immune–podocyte communication is largely unexplored. Here, we investigated whether ANGPTL3 upregulation in podocytes activates macrophages through macrophage scavenger receptor 1 (MSR1) and promotes an interferon-biased inflammatory program in LN.

To identify receptors mediating ANGPTL3 signaling, we employed a secretome-based protein–protein interaction screening strategy using a cell-based membrane protein library platform. Candidate interactions were prioritized based on binding signals and biological relevance to myeloid cells. The ANGPTL3–MSR1 interaction was validated by co-immunoprecipitation in a heterologous expression system. For mechanistic studies, mouse bone marrow–derived macrophages (BMDMs) were generated and stimulated with conditioned media derived from ANGPTL3-overexpressing podocytes. Global transcriptional responses were quantified by RNA sequencing (RNA-seq), and pathway-level changes were assessed by enrichment analyses. To determine receptor dependence, MSR1 was silenced in BMDMs using siRNA prior to ANGPTL3 stimulation, followed by transcriptomic profiling and targeted gene expression assessment. To evaluate in vivo relevance, an inducible lupus-like nephritis model was established by pristane injection, and kidneys were analyzed for glomerular ANGPTL3/MSR1 expression, podocyte integrity markers, macrophage infiltration, and renal functional readouts. Clinical relevance was assessed using Nephroseq datasets and human LN kidney specimens, including evaluation of expression patterns and association with histopathological severity. Single-cell RNA-seq data from public LN kidney datasets were leveraged to localize MSR1 expression to specific renal immune cell populations.

Using membrane protein library screening, ANGPTL3 was identified as an MSR1-interacting ligand, and the interaction was further supported by co-immunoprecipitation, establishing MSR1 as a previously unrecognized receptor candidate for ANGPTL3 in the myeloid compartment. In vitro stimulation of BMDMs with ANGPTL3-conditioned media induced a prominent interferon-dominant transcriptional response, including increased expression of IFN-I–responsive genes such as Tnip3 and Isg20, together with enrichment of interferon-related signaling pathways. In contrast, canonical M1/M2 polarization markers showed minimal changes under these conditions, suggesting that ANGPTL3 preferentially regulates interferon-associated macrophage programs rather than broadly shifting polarization states. Importantly, MSR1 silencing attenuated ANGPTL3-driven interferon gene induction and reduced interferon pathway enrichment, supporting receptor-dependent activation and strengthening the specificity of the ANGPTL3–MSR1 axis in mediating this interferon-biased response. Clinically, analyses of Nephroseq datasets and human LN biopsies demonstrated increased ANGPTL3 and MSR1 expression in LN kidneys compared with controls, with expression levels correlating with histopathological severity. Single-cell RNA-seq analyses further confirmed MSR1 enrichment in glomerular macrophage populations, consistent with its role as a macrophage-associated receptor in inflamed renal tissue. In vivo, pristane-induced lupus mice developed proteinuria and glomerular injury accompanied by increased glomerular ANGPTL3 signal, loss of podocyte markers (including synaptopodin), and enhanced macrophage infiltration. Co-localization of F4/80 and MSR1 in glomeruli supported the presence of an MSR1-positive macrophage subset in injured regions, aligning with a pathogenic podocyte–macrophage axis in lupus-like nephritis.

This study identifies the ANGPTL3–MSR1 axis as a critical pathway linking podocyte injury to macrophage-driven, interferon-biased inflammation in LN. By defining MSR1 as a functional receptor candidate for ANGPTL3 and demonstrating receptor-dependent induction of interferon programs in macrophages, our findings provide mechanistic insight into maladaptive immune–podocyte crosstalk. Targeting ANGPTL3–MSR1 signaling may offer a novel strategy to disrupt macrophage interferon activation and mitigate glomerular injury, with potential therapeutic relevance for LN.