Pathological Effects of IL-17A on Renal Leukocyte Infiltration in Murine Septic AKI (SAKI)

Background: There are no specific treatments for SAKI. Hyperinflammation in kidney leads to renal leukocyte infiltration, which contributes to SAKI. In non-septic AKI, neutrophils and NK cells are first recruited to kidney, followed by inflammatory monocytes. However, the course of renal leukocyte infiltration in SAKI has not been clarified. We have shown that knockout of IL-17A improved survival and SAKI after cecal ligation and puncture (CLP) surgery. We next focused on the downstream of IL-17A. It is well known that IL-17A stimulates non-myeloid cells, such as epithelial cells, to produce chemokines that promotes leukocyte recruitment to inflammatory site. We hypothesized that IL-17A contributes to the pathogenesis of SAKI by promoting leukocyte infiltration into kidney. Methods: IL-17A knockout (IL-17AKO) or wild type mice (WT) were subjected to CLP to induce polymicrobial sepsis or sham surgery. We assessed leukocyte (neutrophil, macrophage, NK cell, B cell, and T cell) infiltration into kidney by flow cytometry and IL-17A, CXCL-1, and -2 concentration in kidney tissue by ELISA at 3, 6, and 18 h after CLP. We also assessed whether recombinant human IL-17A can promote production of human IL-8, a functional homolog of murine CXCL-1 and -2 and a potent promoter of neutrophil recruitment, in HK-2 (human kidney 2) cells in vitro. Results: In WT, CLP upregulated neutrophil and B cell infiltration into kidney at 3 h; neutrophil, NK cell, and T cell infiltration at 6 and 18 h after CLP. IL-17AKO attenuated neutrophil and macrophage infiltration at 3 h and neutrophil, macrophage, and NK cell infiltration at 18 h after CLP. CLP upregulated IL-17A, CXCL-1, and -2 production in kidney tissue at 18 h after CLP, which is significantly decreased by IL-17AKO. Recombinant IL-17A promoted human IL-8 production in HK-2 cells. Conclusion: We have shown that in SAKI, first neutrophils and B cells infiltrated into kidney, followed by NK cells and T cells; IL-17A contributed to neutrophil, NK cell, and macrophage infiltration. IL-17A promoted CXCL-1 and -2 production in kidney. These findings indicates that IL-17A promotes neutrophil infiltration via CXCL-1 and -2 production in kidney after CLP. We are planning further studies to determine how IL-17A promotes NK cell or macrophage infiltration into kidney after CLP.