Sabapathy Vikram, Price Airi, Cheru Nardos Tesfaye, Venkatadri Rajkumar, Dogan Murat, Costlow Gabrielle, Mohammad Saleh, Sharma Rahul
Division of Nephrology, Department of Medicine, Center for Immunity, Inflammation and Regenerative Medicine (CIIR), University of Virginia, Charlottesville, Virginia.
Department of International Health, Georgetown University, Washington, DC.
J Am Soc Nephrol. 2025 Jan 1;36(1):73-86. doi: 10.1681/ASN.0000000000000471. Epub 2024 Aug 26.
IL-33/ST2 alarmin pathway regulates inflammation, fibrosis, and resolution of ischemia-reperfusion injury of kidneys. ST2 regulates the transcriptome of T-regulatory cells related to suppressive and reparative functions. The secretome of ST2 T-regulatory cells regulates hypoxic injury in an amphiregulin-dependent manner.
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.
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.
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 , 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.
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 . Lack of ST2 or AREG in Tregs worsened kidney injury. Tregs protected KDOs from hypoxia in a ST2- and AREG-dependent manner.
白细胞介素-33（IL-33）/ST2警报素通路调节肾脏缺血再灌注损伤的炎症、纤维化及损伤修复。ST2调节与抑制和修复功能相关的调节性T细胞（Treg）的转录组。ST2 Treg的分泌组以双调蛋白依赖的方式调节缺氧损伤。
炎症是肾损伤的主要原因。IL-1家族细胞因子IL-33从受损细胞释放，并通过其在包括调节性T细胞（Tregs）在内的多种细胞类型上表达的受体ST2调节免疫反应。尽管有人提出IL-33具有促炎作用，但外源性IL-33可使Tregs扩增并抑制肾脏炎症。然而，内源性IL-33/ST2对Tregs在肾损伤修复中作用的贡献尚未得到研究。
我们使用小鼠肾脏缺血再灌注损伤和肾脏类器官（KDOs），通过靶向缺失来明确ST2和双调蛋白（AREG）在Tregs中的具体作用。分别对脾脏中经流式分选的Tregs和缺血后肾脏中的CD4 T细胞进行大量RNA测序和单细胞RNA测序。使用同基因KDOs和Tregs在缺氧条件下的新型共培养系统分析ST2充足的Tregs的保护作用。
脾脏的大量RNA测序和肾脏CD4 T细胞的单细胞RNA测序显示，ST2 Tregs富含与Treg增殖和功能相关的基因。修复因子相关基因，如……，在ST2 Tregs中也有富集。在单侧缺血再灌注损伤模型中，Treg特异性缺失ST2或AREG会加剧肾脏损伤和纤维化。在共培养研究中，野生型而非ST2缺陷型Tregs可保留缺氧诱导的肾脏类器官活力丧失，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修复肾损伤中的作用。ST2 Tregs的转录组富含包括……在内的修复因子。Tregs中缺乏ST2或AREG会加重肾脏损伤。Tregs以ST2和AREG依赖的方式保护KDOs免受缺氧影响。
