Intestinal CXCR6+ ILC3s migrate to the kidney and exacerbate renal fibrosis via IL-23 receptor signaling enhanced by PD-1 expression.

Group 3 innate lymphoid cells (ILC3s) regulate inflammation and tissue repair at mucosal sites, but whether these functions pertain to other tissues—like the kidneys—remains unclear. Here, we observed that renal fibrosis in humans was associated with increased ILC3s in the kidneys and blood. In mice, we showed that CXCR6+ ILC3s rapidly migrated from the intestinal mucosa and accumulated in the kidney via CXCL16 released from the injured tubules. Within the fibrotic kidney, ILC3s increased the expression of programmed cell death-1 (PD-1) and subsequent IL-17A production to directly activate myofibroblasts and fibrotic niche formation. ILC3 expression of PD-1 inhibited IL-23R endocytosis and consequently amplified the JAK2/STAT3/RORγt/IL-17A pathway that 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. [Display omitted] • ILC3s migrate from the gut to the injured kidney via the CXCR6-CXCL16 axis • ILC3s trigger renal fibrosis through PD-1-dependent IL-17A production • PD-1 inhibits IL-23R endocytosis on ILC3 to amplify JAK2/STAT3/RORγt/IL-17A pathway Infiltrating immune cells are important contributors to tissue fibrosis. Here, Liang et al. reveal that intestinal ILC3s migrate to the kidney via CXCR6/CXCL16 during renal fibrosis. Within the kidney, immigrated ILC3s express PD-1, which regulates IL-23 receptor endocytosis and enhances IL-17A production, thus exacerbating the fibrotic niche. [ABSTRACT FROM AUTHOR]