Epithelial/Dendritic Cell Cross-Talk in Acute Kidney Injury

描述（由申请人提供）：急性肾功能衰竭（ARF）是一种死亡率极高的常见疾病。炎症在ARF的发病机制中起重要作用。然而，在这种情况下，肾脏损伤激活炎症反应的机制以及先天免疫反应转化为适应性免疫反应的机制仍然知之甚少。本应用程序的目的是确定的机制，侮辱，导致肾脏损伤煽动炎症反应。（TLR）是一个受体家族，通过识别病原体相关的分子模式和组织损伤的内源性信号，作为先天防御的第一道防线。树突状细胞是一种特化的移行抗原呈递细胞，在外周组织中作为哨兵被发现。我们的中心假设是，损伤的肾上皮细胞和涉及TLR4的树突状细胞之间的串扰导致ARF的先天性炎症反应。这一假设是基于我们大量的初步数据，这些数据清楚地表明树突状细胞和TLR4在缺血性和顺铂诱导的ARF中都起着重要作用。我们计划通过追求以下具体目标来验证我们的假设并实现本应用的目标：#1)确定细胞损伤导致肾上皮细胞炎症表型的途径。我们的工作假设是，肾上皮细胞中的TLR4通路在损伤期间被激活，导致促炎细胞因子的产生；#2)确定ARF期间肾树突状细胞活化的机制。我们的工作假设是，在正常情况下，肾上皮细胞主动抑制肾树突状细胞的活性，但这种抑制被损伤过程中产生的促炎细胞因子环境所克服。这项工作具有创新性，因为树突状细胞在ARF中的作用及其与肾上皮细胞的相互作用在很大程度上是未知的。我们的期望是，这些结果将为肾脏的初始损伤引起炎症和随后的结构和功能损伤加剧的机制提供新的见解。这一信息对于更全面地了解急性肾损伤的机制至关重要，包括可能限制损伤的内源性机制。公共卫生相关性：拟议的研究将阐明toll样受体4和肾树突状细胞在急性损伤期间诱导肾脏炎症表型中的关键作用。这些结果将具有相关性，因为它们有望导致临床试验，以测试目前正在开发的TLR4拮抗剂和其他用于预防或治疗急性肾损伤的免疫调节策略的有效性。

DESCRIPTION (provided by applicant): Acute renal failure (ARF) is a common disorder with an exceedingly high mortality rate. Inflammation plays an important role in the pathogenesis of ARF. However, the mechanisms by which renal injury activates an inflammatory response and the mechanisms by which innate immune responses are translated into adaptive immune responses in this setting remain poorly understood. The objective of this application is to determine the mechanisms by which insults which lead to renal injury incite an inflammatory response. (TLR) are a family of receptors positioned as a first line of innate defense by recognizing pathogen-associated molecular patterns and endogenous signals of tissue injury. Dendritic cells are specialized migratory antigen presenting cells found as sentinels in peripheral tissues. Our central hypothesis is that crosstalk between injured renal epithelial cells and dendritic cells involving TLR4 results in innate inflammatory responses in ARF. This hypothesis is based on our extensive preliminary data which clearly indicate that dendritic cells and TLR4 play an important role in both ischemic and cisplatin-induced ARF. We plan to test our hypothesis and achieve the objective of this application by pursuing the following specific aims: #1) Identify the pathways by which cell injury leads to an inflammatory phenotype in renal epithelial cells. Our working hypothesis is that the TLR4 pathway in renal epithelial cells is activated during injury and results in the production of pro-inflammatory cytokines; #2) Determine the mechanism of activation of renal dendritic cells during ARF. Our working hypothesis is that under normal conditions renal epithelial cells actively suppress renal dendritic cell activity but that this suppression is overcome by the pro- inflammatory cytokine milieu produced during injury. The proposed work is innovative because the role of dendritic cells and their interactions with renal epithelial cells in ARF is largely unknown. Our expectation is that the results will provide novel insights into the mechanisms whereby initial insults to the kidney provoke inflammation and subsequent exacerbation of structural and functional damage. This information is vital to a more complete understanding of the mechanisms of acute renal injury including endogenous mechanisms which may act to limit injury. PUBLIC HEALTH RELEVANCE: The proposed studies will elucidate the key role of Toll-like receptor 4 and kidney dendritic cells in the induction of the inflammatory phenotype of the kidney during acute injury. These results will be relevant because they are expected to lead to clinical trials to test the efficacy of TLR4 antagonists currently under development and other immunomodulatory strategies for the prevention or treatment of acute renal injury.