肾
炎症
医学
促炎细胞因子
急性肾损伤
白细胞介素33
纤维化
免疫学
安非雷古林
调节性T细胞
肾缺血
免疫系统
癌症研究
细胞因子
T细胞
再灌注损伤
白细胞介素
缺血
受体
白细胞介素2受体
内科学
生长因子
作者
Vikram Sabapathy,AJ Price,Nardos Tesfaye Cheru,Rajkumar Venkatadri,Murat Doğan,Gabrielle Costlow,Saleh Mohammad,Rahul Sharma
出处
期刊:Journal of The American Society of Nephrology
日期:2024-08-26
标识
DOI:10.1681/asn.0000000000000471
摘要
Background: Inflammation is a major cause of kidney injury. The Interleukin (IL)-1 family cytokine IL-33 is released from damaged cells and modulates the immune response through its receptor ST2 expressed on many cell types, including regulatory T-cells (Tregs). While a proinflammatory role of IL-33 has been proposed, exogenous IL-33 expanded Tregs and suppressed renal inflammation. However, the contribution of endogenous IL-33/ST2 for the role of Tregs in the resolution of kidney injury has not been investigated. Methods: We used murine renal ischemia-reperfusion injury and kidney organoids to delineate the role of the ST2 and amphiregulin (AREG) specifically in Treg cells using targeted deletion. Bulk and single-cell RNA sequencing was performed on flow-sorted Tregs from spleen and CD4 T-cells from post-ischemic kidneys respectively. The protective role of ST2-sufficient Tregs was analyzed using a novel co-culture system of syngeneic kidney organoids and Treg cells under hypoxic conditions. Results: Bulk RNA-sequencing of splenic and single-cell-RNA-sequencing of kidney T-cells showed that ST2 + Tregs are enriched for genes related to Treg proliferation and function. Genes for reparative factors such as AREG were also enriched in ST2 + Tregs. Treg-specific deletion of ST2 or AREG exacerbated kidney injury and fibrosis in the unilateral ischemia reperfusion injury model. In co-culture studies, WT but not ST2-deficient Tregs preserved the hypoxia-induced loss of kidney-organoid viability, which was restored by AREG supplementation. Conclusions: Our study identified the role of the IL-33/ST2 pathway in Tregs for resolution of kidney injury. The transcriptome of ST2 + Tregs was enriched for reparative factors including AREG. Lack of ST2 or AREG in Tregs worsened kidney injury. Tregs protected kidney organoids from hypoxia in ST2 and AREG-dependent manner. Thus Treg-based approaches could be of benefit for resolution of renal injury.
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