IL-33 attenuates renal fibrosis via group2 innate lymphoid cells

Renal fibrosis is a common pathway in the progression of various kidney diseases and injuries. Unilateral ureteral obstruction (UUO) induces renal fibrosis, and immune responses profoundly affect its pathogenesis. Group2 innate lymphoid cells (ILC2s) are strongly activated by interleukin (IL) -33, which is a member of IL-1 family and recognize as alarmin. ILC2s quickly produce large amounts of type 2 cytokines including IL-5 and IL-13, which are involved in inflammation, tissue homeostasis, and wound healing. However, the relationship between renal fibrosis and ILC2s has been unclear. In the present study, we investigated the roles of the ILC2/L-33 axis in renal fibrosis using a UUO model. We found that kidney ILC2s decreased in UUO-affected kidneys compared with their counterpart kidneys despite IL-33 upregulation. There was no effect of reactive oxygen species or TGF-beta from reduced ILC2 caused by UUO. Pretreatment with IL-33 before UUO induced ILC2s and Tregs in kidneys and alleviated renal fibrosis. Furthermore, this protective effect was maintained even when CD4+T cells was depleted. These findings demonstrated that ILC2s play a predominant role in the suppressive function of renal fibrosis mediated by pretreatment with IL-33. In contrast, post-treatment with IL-33 after UUO increased ILC2s in kidneys but had no therapeutic effect on renal fibrosis. Our findings suggest that ILC2s have potential roles in the prevention of renal fibrosis and can serve as a therapeutic and diagnostic target.

肾纤维化是多种肾脏疾病和损伤进展的常见途径。单侧输尿管梗阻（UUO）可诱导肾纤维化，免疫反应对其发病机制有深远影响。第2组先天性淋巴细胞（ILC2s）可被白细胞介素（IL）-33强烈激活，IL - 33是IL - 1家族成员，被视为一种危险相关分子模式（alarmin）。ILC2s可迅速产生大量2型细胞因子，包括IL - 5和IL - 13，这些因子参与炎症、组织内稳态和伤口愈合。然而，肾纤维化与ILC2s之间的关系尚不清楚。在本研究中，我们利用UUO模型探讨了ILC2/IL - 33轴在肾纤维化中的作用。我们发现，尽管IL - 33上调，但与对侧肾脏相比，UUO受累肾脏中的肾脏ILC2s减少。UUO导致的ILC2减少并未引起活性氧或转化生长因子 - β的变化。在UUO之前用IL - 33预处理可诱导肾脏中的ILC2s和调节性T细胞（Tregs），并减轻肾纤维化。此外，即使去除CD4 + T细胞，这种保护作用仍能维持。这些研究结果表明，ILC2s在IL - 33预处理介导的肾纤维化抑制功能中起主要作用。相反，UUO后用IL - 33后处理可增加肾脏中的ILC2s，但对肾纤维化无治疗作用。我们的研究结果表明，ILC2s在预防肾纤维化方面具有潜在作用，可作为治疗和诊断的靶点。