Epithelial/Dendritic cell cross-talk in acute kidney injury

描述（由申请人提供）：急性肾损伤（阿基）是一种常见且通常致命的事件。炎症在阿基的发病机制中起关键作用。关于限制炎症和降低阿基发生率和/或严重程度的内源性途径，我们知之甚少。我们最近确定，常驻树突状细胞（DC）和内源性IL-10是抗炎和降低阿基的严重程度。此外，树突状细胞的保护作用部分依赖于它们产生IL-10。本申请的目的是描述树突状细胞和内源性IL-10相互作用以降低阿基严重程度的机制。核心假设是肾上皮细胞、树突状细胞和Treg细胞的网络通过TLR受体和IL-10相互作用，形成对急性肾损伤的有效防御。为了保留由局部细胞环境提供的重要背景线索，我们的方法将强调体内模型，通过三个目标对阿基中的抗炎机制进行综合分析。1.确定阿基中树突状细胞（DC）IL-10产生和保护的调节机制。我们假设肾脏树突状细胞产生IL-10并以TLR 4和HO-1依赖的方式在阿基中发挥其抗炎和保护作用。2.确定T细胞在DC和IL-10介导的抗ARF保护中的作用。我们假设，阿基中的常驻树突状细胞保护作用是通过其抑制T细胞的抗原特异性活化和增强Treg细胞产生IL- 10的能力介导的。3.确定介导针对阿基的保护的IL-10的靶点。我们假设IL-10通过激活肾上皮细胞中的细胞存活途径并减少白细胞和上皮细胞中的炎性细胞因子产生来减少阿基。这些研究是独特的，因为它们整合了体外和体内方法，允许定义详细的效应机制，并确认观察结果的病理生理学相关性。这些研究将为这一关键的调控系统提供新的见解。它们不仅将导致对顺铂肾毒性的更全面的理解，而且还将导致对其他形式的阿基的更全面的理解。拟议的研究具有转化基础，因为它们将刺激旨在消除阿基后果的新型临床干预措施的开发。

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is a common and often fatal event. Inflammation plays a key role in the pathogenesis of AKI. Relatively little is known regarding the endogenous pathways which limit inflammation and reduce the incidence and/or severity of AKI. We recently determined that resident dendritic cells (DCs) and endogenous IL-10 are anti-inflammatory and reduce the severity of AKI. Moreover, the protective actions of dendritic cells are partially dependent upon their production of IL-10. The objective of this application is to delineate the mechanisms by which dendritic cells and endogenous IL-10 interact to reduce the severity of AKI. The central hypothesis is that a network of renal epithelial cells, dendritic cells and Treg cells, interacting through TLR receptors and IL-10, form a potent defense against acute kidney injury. In order to preserve the important contextual cues provided by the local cellular environment, our approach will emphasize in vivo models in pursuing an integrated analysis of anti-inflammatory mechanisms active in AKI through three aims. 1. Determine the mechanisms of regulation of dendritic cell (DC) IL-10 production and protection in AKI. We hypothesize that renal dendritic cells produce IL-10 and exert their anti-inflammatory and protective effects in AKI in a TLR4 and HO-1-dependent manner. 2. Determine the role of T cells in DC and IL-10 mediated protection against ARF. We hypothesize that resident dendritic cell protection in AKI is mediated through their ability to suppress antigen-specific activation of T cells and enhance IL- 10 production by Treg cells. 3. Determine the targets of IL-10 which mediate protection against AKI. We hypothesize that IL-10 reduces AKI by activating cell survival pathways in renal epithelial cells and reducing inflammatory cytokine production in both leukocytes and epithelial cells. These studies are unique as they integrate in vitro and in vivo approaches permitting detailed effector mechanisms to be defined and the pathophysiological relevance of the observations to be confirmed. These studies will provide new insights into this critical regulatory system. They will lead not only to a more complete understanding of cisplatin nephrotoxicity but also of other forms of AKI. The proposed studies have a translational underpinning in that they will stimulate the development of novel clinical interventions designed to abrogate the consequences of AKI.