Intestinal ILC3s migrate to the kidney and promote renal fibrosis via PD-1-mediated activation

Group 3 innate lymphoid cells (ILC3s) are enriched in mucosae, regulating inflammation and tissue repair, yet their role in renal fibrosis remains unclear. Here, we reported that renal fibrosis and dysfunction were associated with increased ILC3s in human kidney and blood. Using murine models, we showed that the rapid accumulated ILC3s in the kidney primarily originated from the intestinal mucosa. By performing scRNA-seq of ILC(3)s in kidneys and small intestines at different stage of renal fibrosis, we revealed the characteristic and migratory mechanism of these cells. Within the fibrotic kidney, ILC3s upregulated PD-1 to directly activate myofibroblasts and facilitate fibrotic niche formation by producing IL-17A. We also isolated ILCs from Pdcd1-knockout-UUO3d kidneys to gain the molecular mechanism of how PD-1 influence ILC3s' pro-fibrogenic effect. Collectively, we reveal a hitherto unrecognized migration pathway of ILC3s from the intestine to the kidney and the PD-1-dependent function of ILC3s in promoting renal fibrosis. Overall design: Renal or intestinal ILC(3)s of the WT or Pdcd1-knockout mice were isolated by Fluorescence-activated cell sorting (FACS) according to the specific cell surface markers and analyzed using scRNA-seq.