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-36 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-36 in the renal tubular epithelial cells of a mouse model of unilateral ureteral obstruction (UUO) and related cell models using mechanically induced pressure, oxidative stress, or high mobility group box 1. In contrast, the kidneys of IL-36 receptor (IL-36R) knockout mice exhibit attenuated TILs after UUO. Compared with UUO-treated wild-type mice, UUO-treated IL-36 knockout mice exhibited markedly reduced NLRP3 inflammasome activation and macrophage/T cell infiltration in the kidney and T cell activation in the renal draining lymph nodes. , recombinant IL-36 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 UUO mice, also reduced renal TIL formation in UUO mice. In wild-type mice, 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.

Disrupting the IL-36 and IL-23/IL-17 loop underlies the efficacy of calcipotriol and corticosteroid therapy for psoriasis

“…Particularly, mice deficient of IL-36R or mice with blockade of IL-36R were protected from the Ald-induced IL-23/IL-17 axis and disease development (11,13,15); on the other hand, IL-36R antagonist-deficient (Il36rn -/-) mice showed exacerbated pathologies (15). More recently, it has been also shown that IL-36γ induces IL-23 production from psoriasis macrophages (16) and that IL-36α promotes DC-induced Th17 differentiation (17) or directly induces IL-17 on CD4 + T and γδ T cells (48). Of note, we observed that, in contrast with IL-36α and IL-36γ, IL-36β was not significantly induced in either mouse ( Figure 3A) or human (Figure 4) psoriatic skin.…”

“…More recently, an elevated expression of IL-36 cytokines has been found in epidermal KCs of human psoriatic lesional skin (6)(7)(8)(9), and IL-36 cytokines have been proposed to be a psoriasis signature (10)(11)(12). Mouse studies have also pointed out a key role for IL-36 signaling in driving and amplifying psoriatic inflammation together with IL-23/IL-17 cytokine axis (11,(13)(14)(15)(16)(17).…”

Regulation and function of interleukin‐36 cytokines

“…Expression of IL‐36 is increased in several mouse models of kidney disease including models of chronic glomerulonephritis where the number of IL‐36α‐positive tubules correlated with proteinuria, fibrosis score and the presences of tubulointerstitial lesions, and in the streptozotocin‐induced diabetic model where, the presence of IL‐36α‐positive tubules correlated with the magnitude of renal damage . IL‐36R signaling increased NLRP3 inflammasome and IL‐23/IL‐17 axis activation, as well as BMDC‐mediated T‐cell proliferation and Th17 differentiation suggesting the importance of IL‐36 signaling in renal inflammation and fibrosis of a mouse model of unilateral ureteral obstruction . It has been demonstrated that IL‐36 α and its receptor are expressed in human pancreatic myofibroblasts suggesting the potential role of IL‐36 α in inflammatory responses and tissue remodeling in the pancreas …”

Cooling Down the Hot Potato: Anti-Interleukin 36 Therapy Prevents and Treats Experimental Intestinal Fibrosis

“…3 Recently, IL-36 cytokines (IL-36a, IL-36b, and IL-36g) were identified as potent activators of fibroblasts in the pancreas and kidney, making IL-36 and its downstream signaling pathways a potential target for the treatment of inflammation and fibrosis. 4,5 As a member of the IL-1 family, IL-36 transduces signals via binding to a heterodimeric receptor complex composed of IL36R and its co-receptor IL-1R accessory protein (IL-1RAcP). 6 Previous studies in IBD indicate that IL-36R signaling is activated in the IBD mucosa.…”