Kidney macrophages in human lupus nephritis and mouse models express conserved inflammatory and remodeling gene programs and localize to the same anatomic sub-compartments.

Abstract

Abstract Tissue macrophages promote kidney homeostasis through tightly regulated initiation, maintenance, and resolution of tissue repair. In lupus nephritis (LN), kidney macrophages may drive damage in glomeruli and other kidney sub-compartments leading to proteinuria and fibrosis. Recent single-cell RNA sequencing work uncovered 4 novel kidney macrophage subsets in LN patient biopsies: M2-like “reparative”, “inflammatory”, “phagocytic”, and “resident” subsets. But how macrophage gene programs translate into cellular functions driving proximal tissue damage has been difficult to study because we do not fully understand how mouse models recapitulate human LN. Here, we used single cell RNA sequencing to identify kidney macrophage subsets conserved in human and mouse models of LN. We compared the transcriptomes of macrophages collected from human LN patients at peak clinical disease to those from 4 mouse strains at early and peak clinical disease. We discovered that human “reparative”, “inflammatory”, “phagocytic” subsets were conserved across species. In particular, human “reparative” and mouse resident macrophages shared inflammatory and remodeling programs, expressed interferon stimulated genes, and localized to the same kidney sub-compartments. In nephritic mice, this subset converted to a mixed M1-inflammatory/M2-repair phenotype also observed in humans, thus identifying potential conserved programs driving tissue damage in mice and humans. These findings strongly support shared roles for conserved human and mouse macrophages. Critically, they open a new path utilizing mice to study how conserved programs translate into cellular functions driving proximal tissue damage.