A Human-Mouse Atlas of Intrarenal Myeloid Cells in Lupus Nephritis Identifies Conserved Disease-Associated Macrophages

Monocytes and macrophages in patients with lupus nephritis exhibit altered behavior compared to healthy kidneys. How to optimally use mouse models to develop treatments targeting these cells is poorly understood. This study compared intrarenal myeloid cells in four mouse models and 155 lupus nephritis patients using single-cell profiling, spatial transcriptomics, and functional studies. Across mouse models, monocyte and macrophage subsets consistently expanded or contracted in disease. A subset of murine classical monocytes expanded in disease; these cells, expressed Cd9, Spp1, Ctsd, Cd63, Apoe, and Trem2, genes associated with tissue injury in other organs and that play roles in inflammation, lipid metabolism, and tissue repair. Resident macrophages expressed similar genes in clinical disease. In humans, we identified analogous disease-associated monocytes and macrophages that were associated with kidney histological subtypes and disease progression, sharing gene expression and localizing to similar kidney microenvironments as in mice. This cross-species analysis supports the use of mouse functional studies for understanding human lupus nephritis. This experimental study investigated lupus nephritis using two types of mouse models: male mice with Tlr7-overexpression (B6.Sle1.Yaa and NZW/BXSB strains) and female mice with lymphoid-expansion (NZB/W and MRL/lpr strains) before and after the onset of clinical nephritis. To monitor disease, urine samples were collected biweekly for proteinuria assessment and blood samples taken for BUN levels. Clinical nephritis was defined as fixed proteinuria >300mg/dl for two weeks, while mice with BUN >30 mg/dl were excluded for terminal renal failure. For kidney analysis, mice were perfused with PBS, their kidneys harvested and dissociated into single-cell suspensions, and myeloid or CD45+ cells isolated using magnetic beads for flow cytometry or FACS sorting. (contributor) The Kidney Precision Medicine Project (contributor) The Accelerating Medicines Partnership RA-SLE network