Spatially distinct macrophage subsets drive myofibroblast heterogeneity and maladaptive fibrosis in lupus nephritis

Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE), leading to progressive renal fibrosis and functional decline. Understanding the interplay between immune cells and stromal cells is needed to develop effective therapeutic strategies. In this study, we investigated the landscape of macrophage-fibroblast interactions in human LN and validated these findings in mouse models.

We characterised distinct fibroblast subsets and their interactions with renal macrophages using single-cell RNA sequencing of 156 human LN biopsies and 30 healthy controls from the Accelerating Medicines Partnership-SLE cohort, and spatial transcriptomics of biopsies from 6 patients with LN. In vitro coculture studies using mouse models were performed to further define functional consequences of these interactions.

We identified 2 myofibroblast subsets: a proinflammatory subset (Myofib1) enriched in the tubulointerstitium, and a fibrotic/remodelling subset (Myofib2) in glomeruli, both correlating with the histologic chronicity index. Spatial transcriptomics revealed different colocalisation patterns, with Myofib1 interacting with activated resident macrophage (RM) subsets and Myofib2 with glomerular infiltrating disease-associated macrophages. In vitro coculture studies demonstrated that nephritic RMs promote a proinflammatory, remodelling fibroblast phenotype that impairs wound healing and drives a Myofib1-like gene programme, whereas disease-associated macrophages generated profibrotic fibroblasts with dysregulated reparative capacity. Cell-cell communication analyses identified key ligand-receptor interactions mediating this crosstalk, including Spp1/integrins, Sema4/PlexinB, and nicotinamide phosphoribosyl transferase/INSR.

Our data reveal a spatially and functionally heterogeneous landscape of macrophage-fibroblast crosstalk in LN. These findings advance our understanding of renal fibrogenesis in LN, highlighting specific fibroinflammatory circuits that may represent therapeutic targets to prevent chronic renal damage.