State Key Laboratory of Kidney Disease, Department of Nephrology, Chinese PLA General Hospital and Military Medical Postgraduate College, Beijing, China; Department of Nephrology, Xijing Hospital, the Fourth Military Medical University, Xi'an, China.
State Key Laboratory of Kidney Disease, Department of Nephrology, Chinese PLA General Hospital and Military Medical Postgraduate College, Beijing, China.
Kidney Int. 2018 Apr;93(4):814-825. doi: 10.1016/j.kint.2017.08.030. Epub 2017 Nov 11.
Mesenchymal stem cells (MSCs) are effective for the management of experimental ischemia-reperfusion acute kidney injury (IRI-AKI). Immune modulation is one of the important mechanisms of MSCs treatment. Interleukin-17A (IL-17A) pretreated MSCs are more immunosuppressive with minimal changes in immunogenicity in vitro. Here, we demonstrated that administration of IL-17A-pretreated MSCs resulted in significantly lower acute tubular necrosis scores, serum creatinine, and BUN of mice with IRI-AKI, compared with the administration of MSCs. Of the co-cultured splenocytes, IL-17A-pretreated MSCs significantly increased the percentages of CD4Foxp3 Tregs and decreased concanavalin A-induced T cell proliferation. Furthermore, mice with IRI-AKI that underwent IL-17A-pretreated MSC therapy had significantly lower serum IL-6, TNF-α, and IFN-γ levels, a higher serum IL-10 level, and higher spleen and kidney Treg percentages than the mice that underwent MSCs treatment. Additionally, the depletion of Tregs by PC61 (anti-CD25 antibody) reversed the enhanced treatment efficacy of the IL-17A-pretreatedMSCs on mice with IRI-AKI. Additionally, IL-17A upregulated COX-2 expression and increased PGE2 production. The blockage of COX-2 by celecoxib reversed the benefit of IL-pretreated 17A-MSCs on the serum PGE2 concentration, spleen and kidney Tregs percentages, serum creatinine and BUN levels, renal acute tubular necrosis scores, and serum IL-6, TNF-α, IFN-γ, and IL-10 levels of IRI-pretreated mice with AKI, compared with MSCs. Thus, our results suggest that IL-17A pretreatment enhances the efficacy of MSCs on mice with IRI-AKI by increasing the Treg percentages through the COX-2/PGE2 pathway.
间充质干细胞（MSCs）可有效治疗实验性缺血再灌注急性肾损伤（IRI-AKI）。免疫调节是 MSCs 治疗的重要机制之一。与 MSCs 相比，IL-17A（IL-17A）预处理的 MSCs 在体外具有更低的免疫原性和更高的免疫抑制作用。在此，我们证明与 MSC 治疗相比，给予 IL-17A 预处理的 MSC 可使 IRI-AKI 小鼠的急性肾小管坏死评分、血清肌酐和 BUN 显著降低。在共培养的脾细胞中，IL-17A 预处理的 MSC 显著增加了 CD4Foxp3 Treg 的比例，并降低了刀豆蛋白 A 诱导的 T 细胞增殖。此外，接受 IL-17A 预处理 MSC 治疗的 IRI-AKI 小鼠的血清 IL-6、TNF-α 和 IFN-γ 水平显著降低，血清 IL-10 水平显著升高，脾和肾 Treg 比例也显著升高，而接受 MSC 治疗的小鼠则相反。此外，通过 PC61（抗 CD25 抗体）耗竭 Treg 可逆转 IL-17A 预处理 MSC 对 IRI-AKI 小鼠治疗效果的增强。此外，IL-17A 上调 COX-2 的表达并增加 PGE2 的产生。通过塞来昔布阻断 COX-2 可逆转 IL-17A 预处理 MSC 对 IRI-AKI 小鼠血清 PGE2 浓度、脾和肾 Treg 比例、血清肌酐和 BUN 水平、肾急性肾小管坏死评分以及血清 IL-6、TNF-α、IFN-γ 和 IL-10 水平的有益作用，与 MSC 相比。因此，我们的结果表明，IL-17A 预处理通过 COX-2/PGE2 途径增加 Treg 比例，增强了 MSCs 对 IRI-AKI 小鼠的疗效。
