IFN-γ-dominant immune shift is associated with reduced protective ILC2 responses in chronic kidney disease.

Chronic kidney disease (CKD) progression is driven by an imbalance between inflammatory injury and tissue repair; however, the immune mechanisms that disrupt reparative pathways remain incompletely understood. Group 2 innate lymphoid cells (ILC2s) play protective roles in epithelial integrity and antifibrotic responses in the kidney, yet the signals that limit their maintenance during chronic inflammation are unclear. In this study, we investigated whether interferon-γ (IFN-γ)-dominant immune polarization is associated with the loss of renal ILC2s and exacerbation of CKD. Using a murine model of adenine-induced CKD, administration of α-galactosylceramide (αGalCer), a glycolipid known to activate invariant NKT cells, exacerbated renal dysfunction and tubulointerstitial injury. This was accompanied by enhanced inflammatory responses and a shift toward a type 1-dominant immune milieu. Notably, αGalCer treatment was associated with reduced renal ILC2 and regulatory T cell abundance, along with suppression of type 2 cytokines. Time-course analysis revealed a rapid and transient increase in renal Ifng expression following αGalCer administration, suggesting an early cytokine-driven immune shift. Neutralization of IFN-γ ameliorated kidney injury, restored ILC2 abundance, and partially rebalanced the renal immune environment. These findings suggest that IFN-γ-dominant immune polarization is associated with suppression of protective ILC2 responses and exacerbation of CKD. Further investigation of IFN-γ-mediated immune imbalance may provide insights into therapeutic strategies aimed at preserving protective ILC2 responses in CKD.