Macrophage Function in Kidney Repair

描述（由申请方提供）：急性肾损伤（阿基）是住院患者的常见事件。损伤导致局部和全身反应，以去除受损的肾小管细胞并刺激存活的细胞重建正常的肾小管结构。研究 使用多种啮齿动物肾损伤模型的研究表明，巨噬细胞在损伤后在肾中逐渐积累，并经历从促炎（M1样）表型到发生正常修复所需的交替活化（M2样）表型的转变。然而，在体内调节M1到M2转变的信号，以及促进正常修复的实际M2衍生因子，都是未知的。我们的数据表明，从促炎性表达到替代激活的转换可以通过激活2个不同的信号传导途径（Stat 3和Stat 6）与促炎性TLR依赖性M1激活途径（MyD 88/NFkB）和炎性小体的次级信号传导协调发生。此外，我们发现肾小管细胞分泌/脱落内源性TLR配体沿着gp 130/Stat 3激活剂Lif以激活这些信号传导事件。对在M1-M2转变时从受损肾脏分离的巨噬细胞的分析揭示了两种蛋白质Arg 1和Brp 39的表达增加>100倍，这两种蛋白质都强烈地涉及促进肾小管细胞存活和增殖。本提案中描述的研究旨在鉴定在M1-M2转换（Aim 1）期间调节Arg 1和Brp 39表达的体外信号传导事件，以确定这些途径对这些修复因子表达以及抑制肾小管损伤和促进小鼠和人阿基修复的体内重要性（Aim 2），并进行选择性的体外和体内巨噬细胞致敏作为促进急性肾损伤后修复的治疗方法。 公共卫生相关性：肾脏可能会受伤并停止功能，但它们有能力用新的细胞取代受损的细胞，从而恢复功能。我们已经确定巨噬细胞作为这个修复过程的一个突出的调节器。我们目前的建议集中在了解巨噬细胞如何促进肾脏修复，并开发使用它们进行治疗的方法。

DESCRIPTION (provided by applicant): 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 using multiple rodent models of kidney injury have shown that macrophages progressively accumulate in the kidney after injury and undergo a transition from a proinflammatory (M1-like) phenotype to an alternatively activated (M2-like) phenotype that is required for normal repair to occur. However, 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 as yet unknown. Our data demonstrate that the switch from proinflammatory expression to alternative activation can occur via activation of 2 distinct signaling pathways (Stat3 and Stat6) in coordination with secondary signaling by the proinflammatory TLR-dependent M1 activation pathway (MyD88/NFkB) and the inflammasome. Furthermore, we have found that tubular cells secrete/shed endogenous TLR ligands along with the gp130/Stat3 activator Lif to activate these signaling events. 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 vitro signaling events that regulate Arg1 and Brp39 expression during M1-M2 transition (Aim1), to define the in vivo importance of those pathways for the expression of these reparative factors and for suppressing tubule injury and promoting repair in murine and human AKI (Aim 2), and to perform selective in vitro and in vivo macrophage priming as a therapeutic approach to promote repair after acute kidney injury. PUBLIC HEALTH RELEVANCE: The kidneys can be injured and stop functioning, yet they have the ability to replace the damaged cells with new ones and thus restore function. We have identified macrophages as a prominent regulator of this repair process. Our current proposal is focused on learning how macrophages promote kidney repair and developing approaches to use them for therapy.