Macrophage Function in Kidney Repair

急性肾损伤(AKI)是住院患者的常见病。受伤导致局部和 清除受损肾小管细胞并刺激存活细胞重建正常肾小管的系统反应 小管结构。在啮齿动物肾脏损伤模型和人类活检组织中的研究表明， 巨噬细胞在损伤后积聚在肾脏中，并经历了从促炎症(类M1)的转变 表型转变为正常修复所需的交替激活的(类M2)表型。这些信号表明 在体内调节M1到M2转换，以及促进正常的实际M2衍生因子 因此，人们对维修非常感兴趣。我们的体外和体内数据显示，从促炎切换到 通过一种新的途径表达到交替激活，在该途径中，肾小管细胞分泌GM-CSF和 DAMPS通过TLR2/4/MyD88协同二级信号通路诱导巨噬细胞Stat5活化 途径(MyD88/NFκB)。M1-M2期损伤肾脏巨噬细胞的分离分析 转换显示Arg1和Brp39这两种蛋白质的表达增加了100倍，这两种蛋白质都是 与促进肾小管细胞存活和增殖有关。这项提案中描述的研究包括 旨在确定GM-CSF/Stat5信号在体内抑制炎性巨噬细胞中的作用 激活和诱导交替激活(Aim1)，并确定GM-CSF/Stat5和 DAMPS/TLR2/4协同诱导Arg1和Brp39表达抑制肾小管损伤 促进修复(目标2)。这些结果将用于指导巨噬细胞的体外和体内启动。 急性肾损伤后抑制肾小管损伤和促进修复的治疗方法(目标1和2)。

Acute Kidney Injury (AKI) is a common occurrence in hospitalized patients. The injury leads to both local and systemic responses to remove damaged tubular cells and stimulate surviving cells to reconstitute the normal tubule architecture. Studies in rodent models of kidney injury and in human biopsies have shown that macrophages accumulate in the kidney after injury and undergo a transition from a proinflammatory (M1-like) phenotype to the alternatively activated (M2-like) phenotype that is required for normal repair. The signals that regulate that M1 to M2 transition in vivo, as well as the actual M2-derived factors that are promoting normal repair, are therefore of great interest. Our in vitro and in vivo data show that the switch from proinflammatory expression to alternative activation occurs via a novel pathway in which tubular cell secreted GM-Csf and DAMPs induce macrophage Stat5 activation in coordination with secondary signaling by the TLR2/4/MyD88 pathway (MyD88/NFκB). Analysis of macrophages isolated from injured kidneys at the time of M1-M2 transition reveals >100-fold increase in expression of two proteins, Arg1 and Brp39, both of which are strongly implicated in promoting tubular cell survival and proliferation. The studies described in this proposal are designed to identify the in vivo role of GM-Csf/Stat5 signaling in suppressing inflammatory macrophage activation and inducing alternative activation (Aim1), and to define the mechanism by which GM-Csf/Stat5 and DAMPs/TLR2/4 coordinately induce the expression of Arg1 and Brp39 for suppressing tubule injury and promoting repair (Aim 2). These results will be used to guide the in vitro and in vivo priming of macrophages as a therapeutic approach to suppress tubular injury and promote repair after acute kidney injury (Aims 1 and 2).