y in an amphiregulin-dependent manner. Background Inflammation is a major cause of kidney injury. 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). Although 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 (KDOs) to delineate the role of the ST2 and amphiregulin (AREG) specifically in Tregs using targeted deletion. Bulk and single-cell RNA sequencing were performed on flow-sorted Tregs from spleen and CD4 T cells from postischemic kidneys, respectively. The protective role of ST2-sufficient Tregs was analyzed using a novel coculture system of syngeneic KDOs and Tregs under hypoxic conditions. Results Bulk RNA sequencing of splenic and single-cell RNA sequencing of kidney CD4 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 coculture studies, wild-type but not ST2-deficient Tregs preserved 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 KDOs from hypoxia in a ST2- and AREG-dependent manner....

中文翻译：

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缺血性肾损伤后肾脏炎症和纤维化中的 ST2+ T 调节细胞


y 以两调蛋白依赖性方式。背景 炎症是肾损伤的主要原因。IL-1 家族细胞因子 IL-33 从受损细胞中释放，并通过其在许多细胞类型（包括调节性 T 细胞 （Tregs））上表达的受体 ST2 调节免疫反应。尽管已经提出 IL-33 的促炎作用，但外源性 IL-33 会扩大 Tregs 并抑制肾脏炎症。然而，内源性 IL-33/ST2 对 Tregs 在肾损伤消退中的作用的贡献尚未得到研究。方法 我们使用小鼠肾缺血再灌注损伤和肾脏类器官 （KDO） 来描述使用靶向缺失在 Tregs 中特异性 ST2 和两性调节蛋白 （AREG） 的作用。分别对来自脾脏的流式分选 Tregs 和来自缺血后肾脏的 CD4 T 细胞进行大量和单细胞 RNA 测序。在缺氧条件下，使用同基因 KDO 和 Treg 的新型共培养系统分析 ST2 充足的 Tregs 的保护作用。结果 肾 CD4 T 细胞脾脏批量 RNA 测序和单细胞 RNA 测序显示，ST2+ Tregs 富集了与 Treg 增殖和功能相关的基因。修复因子的基因，如 Areg，也在 ST2 + Tregs 中富集。ST2 或 AREG 的 Treg 特异性缺失加剧了单侧缺血再灌注损伤模型中的肾损伤和纤维化。在共培养研究中，野生型但非 ST2 缺陷型 Tregs 保留了缺氧诱导的肾类器官活力丧失，这种活力通过补充 AREG 而恢复。结论 我们的研究确定了 Tregs 中 IL-33/ST2 通路对肾损伤消退的作用。ST2 + Tregs 的转录组富含包括 Areg 在内的修复因子。 Tregs 中缺乏 ST2 或 AREG 会加重肾损伤。Tregs 以 ST2 和 AREG 依赖性方式保护 KDO 免受缺氧。