Regulation of kidney fibrosis by ILC3s via a gut–kidney axis

Innate lymphoid cells (ILCs) are lymphocytes that regulate immune responses. Little is known about these cells in the kidney. New findings now reveal a role for group 3 ILCs (ILC3s) in regulating kidney fibrosis, following their migration from the intestine via a CXCR6–CXCL16 signalling axis.

Using single-cell RNA sequencing of genetic models combined with structural predictions of molecular interactions, the researchers demonstrated that PD-1, expressed by newly migrated ILC3s, enhances the production of IL-17A (an ILC3 effector cytokine), which promotes kidney fibroblast activation to induce fibrosis. Mechanistically, expression of PD-1 by ILC3s impedes the endocytosis of IL-23R by binding competitively to it. The resulting surface expression of IL-23R enables IL-23-induced signalling through the JAK2–STAT3–RORγt pathway to induce IL-17A release.