IL-36 signaling facilitates activation of the NLRP3 inflammasome and IL-23/IL-17 Axis in renal inflammation and fibrosis

Abstract

IL-36 cytokines are proinflammatory and have an important role in innate and adaptive immunity, but the role of IL-36 signaling in renal tubulointerstitial lesions (TILs), a major prognostic feature of renal inflammation and fibrosis, remains undetermined. In this study, increased IL-36a expression detected in renal biopsy specimens and urine samples from patients with renal TILs correlated with renal function impairment.We confirmed the increased expression of IL-36a in the renal tubular epithelial cells of amouse model of unilateral ureteral obstruction (UUO) and related cellmodels using mechanically induced pressure, oxidative stress, or highmobility group box 1. In contrast, the kidneys of IL-36 receptor (IL-36R) knockoutmiceexhibit attenuated TILs afterUUO.ComparedwithUUO-treated wild-typemice, UUO-treatedIL- 36knockoutmiceexhibitedmarkedly reducedNLRP3inflammasomeactivationandmacrophage/T cell infiltration in the kidney and T cell activation in the renal draining lymph nodes. In vitro, recombinant IL-36a facilitated NLRP3 inflammasome activation in renal tubular epithelial cells,macrophages, and dendritic cells and enhanced dendritic cell-induced T cell proliferation and Th17 differentiation. Furthermore, deficiency of IL-23, which was diminished in IL-36R knockout UUOmice, also reduced renal TIL formation inUUOmice. Inwild-typemice, administration of an IL-36R antagonist after UUO reproduced the results obtained in UUO-treated IL-36R knockout mice.We propose that IL-36 signaling contributes to the pathogenesis of renal TILs through the activation of the NLRP3 inflammasome and IL-23/IL-17 axis.