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).