Targeting immune dysfunction during transition from AKI to CKD

针对 AKI 向 CKD 过渡期间的免疫功能障碍

• 批准号: 10636189
• 负责人: Leyuan Xu
• 金额: $ 36.85万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10636189
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Adhesions; Atrophic; Attenuated; Bilateral; CCL8 gene; CCR1 gene; CD4 Positive T Lymphocytes; CXCR6 gene; Cell Adhesion; Cell Surface Proteins; Cells; Chronic Kidney Failure; Clinical; Contralateral; Data; Data Set; Dendrimers; Development; Disease; Disease Progression; Disease model; Exhibits; Failure; Fibrosis; Folic Acid; Functional disorder; Home; Homing; Immune; Immune System Diseases; Immune Targeting; In Vitro; Inflammation; Injury; Injury to Kidney; Ischemia; Kidney; Kidney Diseases; Knockout Mice; Lead; Macrophage; Mannose; Mediating; Modeling; Myofibroblast; Neutrophil Infiltration; Organ; PTPRC gene; Pathogenesis; Patients; Pharmaceutical Preparations; Play; Population; Publications; Publishing; Recovery; Renal Hypertension; Reperfusion Injury; Risk; Role; Secondary to; Signal Transduction; Small Interfering RNA; Source; Stains; T cell infiltration; T-Cell Depletion; T-Lymphocyte; Testing; Time; Transgenic Mice; Translating; Tubular formation; Vascular Cell Adhesion Molecule-1; Work; cell type; chemokine; chronic infection; data repository; folate-binding protein; immune activation; improved; in vivo; inflammatory milieu; injured; innovation; interest; kidney biopsy; kidney fibrosis; kidney repair; knock-down; mannose receptor; mouse model; nanoparticle; neutralizing antibody; neutrophil; pharmacologic; pre-clinical; prevent; receptor; recruit; repaired; severe injury; siRNA delivery; single-cell RNA sequencing; targeted delivery; targeted treatment; therapeutic target

Project Summary Acute kidney injury (AKI) significantly increases the risk of developing progressive kidney fibrosis and chronic kidney disease (CKD). T cells and polymorphonuclear neutrophils (PMNs) have been shown involved in pathogenesis of AKI; however, their role(s) during AKI-to-CKD transition remain uncertain. Our recent publication and preliminary data revealed that failure of resolving tubular injury from unilateral ischemia/reperfusion injury (U-IRI, a rapid AKI-to-CKD transition mouse model) led to not only macrophage persistence but also a second wave of T cells and PMNs infiltrating into tubulointerstitium, which closely associated with a proinflammatory milieu. Concomitantly, the tubular cells from U-IRI kidney expressed higher level of injury marker, vascular cell adhesion molecule 1 (Vcam1), and exhibited a dedifferentiated expression profile, correlating with kidney atrophy. Clinically, we found that increasing numbers of T cells and PMNs in the renal interstitium at the time of renal biopsy in patients with AKI negatively correlated with 6-month recovery of GFR. In the U-IRI mouse model, we found that depletion of T cells and PMNs attenuated the second wave of tubular injury and partially restore tubule mass, suggesting that T cells and PMNs promote secondary tubular injury and kidney atrophy, and that blocking T cells and PMNs recruitment can attenuate CKD from AKI. Our chemokine/receptor pair analyses from the scRNA-seq dataset on the IRI kidneys identified that CXCL16 and MCP-2 (Ccl8) are the top homing signals to recruit T cells (CXCR6+) and PMNs (CCR1+) and that persisted macrophages are the primary source of CXCL16 and MCP-2 during AKI-to-CKD transition. Together, these findings have led us to hypothesize that in the setting of failed tubular repair, macrophage-expression of CXCL16 and MCP-2 promotes a second wave of T cells and PMNs infiltrating into the injured kidneys and that tubular VCAM-1 enhances T cells adhesion and retention, which together lead to secondary tubular injury. Thus, targeting the CXCL16/CXCR6 and MCP-2/CCR1 as well as VCAM-1/T cell signaling after kidney injury holds great potential for the treatment of CKD progression. To test this hypothesis, we propose to define the importance of CXCL16/CXCR6 and VCAM-1 signaling in T cell homing and adhesion (SA1) and the importance of MCP-2/CCR1 signaling in PMN homing (SA2) during AKI-to-CKD transition and then to translate our understanding of these homing signals into developing polyamidoamine dendrimer nanoparticles that can selectively deliver siRNAs to knockdown these homing signals to slow or even prevent CKD progression (SA3). This work will provide preclinical data defining how to prevent the second wave of immune activation and transition from AKI to CKD.

项目概要 急性肾损伤（AKI）显着增加发生进行性肾纤维化和慢性肾纤维化的风险 肾脏疾病（CKD）。 T 细胞和多形核中性粒细胞 (PMN) 已被证明参与 AKI 的发病机制；然而，它们在 AKI 向 CKD 转变过程中的作用仍不确定。我们最近的 出版物和初步数据显示，单侧肾小管损伤无法解决 缺血/再灌注损伤（U-IRI，一种快速 AKI 向 CKD 转变的小鼠模型）不仅导致巨噬细胞 持续存在，而且还有第二波 T 细胞和 PMN 渗入肾小管间质，这与 与促炎环境有关。与此同时，来自 U-IRI 肾的肾小管细胞表达更高 损伤标志物血管细胞粘附分子1（Vcam1）的水平，并表现出去分化的表达 轮廓，与肾萎缩相关。临床上，我们发现，T细胞和PMN的数量不断增加 AKI 患者肾活检时肾间质的变化与 6 个月恢复呈负相关 肾小球滤过率。在 U-IRI 小鼠模型中，我们发现 T 细胞和 PMN 的消耗减弱了第二波 肾小管损伤并部分恢复肾小管质量，表明 T 细胞和 PMN 促进继发性肾小管 损伤和肾萎缩，并且阻断 T 细胞和 PMN 募集可以减轻 AKI 引起的 CKD。我们的 对 IRI 肾脏的 scRNA-seq 数据集的趋化因子/受体对分析表明，CXCL16 和 MCP-2 (Ccl8) 是招募 T 细胞 (CXCR6+) 和 PMN (CCR1+) 的顶级归巢信号，并且持续存在 巨噬细胞是 AKI 向 CKD 转变期间 CXCL16 和 MCP-2 的主要来源。在一起，这些 研究结果使我们推测，在肾小管修复失败的情况下，巨噬细胞表达 CXCL16 和 MCP-2 促进第二波 T 细胞和 PMN 渗入受伤的肾脏，并且 肾小管 VCAM-1 增强 T 细胞粘附和保留，共同导致继发性肾小管损伤。 因此，针对肾损伤后的 CXCL16/CXCR6 和 MCP-2/CCR1 以及 VCAM-1/T 细胞信号转导 具有治疗 CKD 进展的巨大潜力。为了检验这个假设，我们建议定义 CXCL16/CXCR6 和 VCAM-1 信号在 T 细胞归巢和粘附 (SA1) 中的重要性以及 MCP-2/CCR1 信号在 AKI 至 CKD 过渡期间 PMN 归巢 (SA2) 中的重要性，然后进行翻译 我们对这些归巢信号的理解有助于开发聚酰胺胺树枝状聚合物纳米颗粒，该纳米颗粒可以 选择性地递送 siRNA 来敲低这些归巢信号，从而减缓甚至阻止 CKD 进展 (SA3)。 这项工作将提供临床前数据，定义如何预防第二波免疫激活和 从 AKI 过渡到 CKD。