Intestinal ILC3s Migrate to the Kidney and Promote Renal Fibrosis via PD-1-mediated Activation

Group 3 innate lymphoid cells (ILC3s) are enriched in mucosa, 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 kidneys and blood. Using murine models, we showed that the rapidly accumulated ILC3s in the kidney primarily originated from the intestinal mucosa. CXCR6 + ILC3s were migrated to the kidney by the chemokine CXCL16 released from the injured tubules. Within the fibrotic kidney, ILC3s increased the expression of programmed death receptor-1 (PD-1) to directly activate myofibroblasts and fibrotic niche formation by producing IL-17A. PD-1 inhibition of IL-23R endocytosis and consequent amplification of JAK2/STAT3/RORγt/IL-17A pathway was essential for the pro-fibrogenic effect of ILC3s. Thus, 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.