A kidney innate – parenchymal module controls autoimmune organ damage
A kidney innate – parenchymal module controls autoimmune organ damage Innate immune activation promotes the susceptibility of target organs to autoimmune organ damage yet the mechanisms by which innate immune and parenchymal cells orchestrate organ damage are unresolved. Here, we unravel an essential role of tissue NKp46+ innate lymphoid cells (ILC) and the activating receptor NKp46 in controlling murine lupus nephritis severity. Unbiased scRNA-seq analysis of the whole kidney cortex revealed the molecular basis of severe disease, including an intermediate parietal epithelial cell (iPEC) - disease-associated macrophage (DAM) module, capillary endothelial de-differentiation, and podocyte loss. Surprisingly, NKp46+ ILC controlled DAM population expansion, thus promoting interstitial inflammation and tissue damage. ScRNA-seq revealed a tissue helper NKp46+ ILC subset expressing cytokines promoting mononuclear phagocyte activation and survival in nephritic kidneys. Thus, an innate-parenchymal module, controlled by tissue NKp46+  helper ILC, amplifies immunopathology with broad implications for autoimmune diseases and viral infections.