Csf2 Attenuated Sepsis-Induced Acute Kidney Injury by Promoting Alternative Macrophage Transition

Sepsis is a systemic inflammatory state in response to infection, and concomitant acute kidney injury (AKI) increases mortality significantly. Macrophages accumulate in the kidney after injury and undergo a transition from a pro-inflammatory (M1) to the alternatively activated (M2) phenotype that is required for normal repair. However, the specific signals that regulate the transition from M1 to M2 in vivo, are unknown. Therefore, we first cocultured human M1 macrophages with HK-2 cells and characterized cytokine /chemokine profiles via Luminex. We found that Csf2 was the most up-regulated protein from a panel of 55. The switch from a pro-inflammatory M1 to M2 occurred via a novel pathway through which Csf2 secreted by tubular cell-induced macrophage Stat5 phosphorylation, which subsequently decreased HK-2 cells apoptosis. Analysis of macrophages in the presence of Csf2 at the time of M1-M2 transition revealed an increment in the expression of M2 markers in a dose-dependent manner. Furthermore, Csf2 antibody intraperitoneal injection after cecal ligation puncture procedure (CLP) attenuated kidney M1-M2 macrophage transition via p-STAT5 signaling and suppressed tubular proliferation, and subsequently decreased survival. These results are clinically significant to guide the priming of macrophages as a therapeutic approach to suppress tubular injury and promote repair after sepsis-induced AKI.