The IL-33/ST2/ILC2 pathway in kidney disease: balancing inflammation, fibrosis, and repair

Abstract

Group 2 innate lymphoid cells (ILC2s) are tissue-resident immune cells that respond rapidly to epithelial-derived cytokines such as interleukin (IL)-33, producing type 2 cytokines including IL-5 and IL-13. Although ILC2s are well recognized for their roles in regulating inflammation and tissue remodeling in barrier organs, their functions in the kidney have only recently gained attention. In this review, we summarize the localization, activation, and effector functions of ILC2s in the kidney and explore their immunoregulatory interactions with macrophages, particularly in promoting M2 polarization. We further provide an overview of the therapeutic relevance of the IL-33/ST2/ILC2 axis in renal pathology, organizing current findings across models of acute kidney injury (AKI), chronic kidney disease (CKD), and glomerulonephritis (GN). ILC2s are primarily distributed in the perivascular tubulointerstitial regions of both the renal cortex and outer medulla, where they exert anti-inflammatory and antifibrotic effects through cytokine-mediated mechanisms. Importantly, recent studies suggest that the outcomes of IL-33-mediated interventions are highly context-dependent, influenced by factors such as dosage, disease phase, and temporal dynamics. A comprehensive understanding of the IL-33/ST2/ILC2 axis may offer new insights into immune modulation and tissue protection strategies for kidney diseases.

Keywords: IL-33/ST2 pathway; M2 macrophage; fibrosis; innate lymphoid cell; kidney disease.