炎症是肾损伤的主要原因。白细胞介素 (IL)-1 家族细胞因子 IL-33 从受损细胞中释放出来，并通过在许多细胞类型（包括调节性 T 细胞 (Treg)）上表达的受体 ST2 调节免疫反应。虽然已提出 IL-33 具有促炎作用，但外源性 IL-33 可以扩大 Tregs 并抑制肾脏炎症。然而，内源性 IL-33/ST2 对 Tregs 在肾损伤缓解中的作用尚未进行研究。我们使用小鼠肾缺血再灌注损伤和肾类器官来描述 ST2 和双调蛋白 (AREG) 的作用特别是在 Treg 细胞中使用靶向删除。分别对来自脾脏的流式分选的 Tregs 和来自缺血后肾脏的 CD4 T 细胞进行了批量和单细胞 RNA 测序。使用同基因肾类器官和 Treg 细胞在低氧条件下的新型共培养系统分析了 ST2 充足的 Tregs 的保护作用。脾脏的批量 RNA 测序和肾 T 细胞的单细胞 RNA 测序表明 ST2 Treg 富含与 Treg 增殖和功能相关的基因。 ST2 Tregs 中也富集了 AREG 等修复因子的基因。在单侧缺血再灌注损伤模型中，Treg 特异性删除 ST2 或 AREG 会加剧肾损伤和纤维化。在共培养研究中，WT（而非 ST2 缺陷型）Treg 保留了缺氧引起的肾类器官活力丧失，通过补充 AREG 可恢复这种活力。我们的研究确定了 IL-33/ST2 通路在 Tregs 中的作用，以解决肾损伤。 ST2 Tregs 的转录组富含包括 AREG 在内的修复因子。 Tregs 中 ST2 或 AREG 的缺乏会加重肾损伤。 Tregs 以 ST2 和 AREG 依赖性方式保护肾脏类器官免受缺氧影响。因此，基于 Treg 的方法可能有益于解决肾损伤。美国肾脏病学会版权所有 © 2024。

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.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.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.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.Copyright © 2024 by the American Society of Nephrology.