Myeloid-Derived Suppressor Cells Ameliorate Cyclosporine A-Induced Hypertension in Mice.
Myeloid-Derived Suppressor Cells Ameliorate Cyclosporine A-Induced Hypertension in Mice.
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DOI：
10.1161/hypertensionaha.117.10306
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发表时间：
2018-01
期刊：
影响因子：
--
通讯作者：
Mitchell BM
中科院分区：
文献类型：
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作者：
Chiasson VL;Bounds KR;Chatterjee P;Manandhar L;Pakanati AR;Hernandez M;Aziz B;Mitchell BM
钙调磷酸酶抑制剂环孢素A抑制免疫系统，但促进高血压，血管功能障碍和肾损伤。环孢菌素A减少调节性T细胞，这有助于高血压的发展。然而，环孢菌素A对另一个重要的调节性免疫细胞亚群，髓源性抑制细胞（MDSC）的影响尚不清楚。我们假设，增加MDSC将改善环孢素A诱导的高血压和血管和肾脏损伤和功能障碍，环孢素A减少小鼠的MDSC。每日白细胞介素-33治疗，增加MDSC水平，完全防止环孢素A诱导的高血压和血管和肾脏毒性。在建立高血压后，将对照小鼠的MDSC连续转移到环孢素A治疗的小鼠中，剂量依赖性地降低血压和血管和肾小球损伤。从对照小鼠中分离的睾丸和肾脏经环孢霉素A处理24小时，分别降低了松弛反应和增加了炎症，并且这些作用被MDSC的存在所阻止。MDSC还阻止了环孢霉素A诱导的微血管和肾小球内皮细胞中纤维连接蛋白的增加。最后，环孢霉素A通过抑制钙调磷酸酶和阻止细胞增殖而剂量依赖性地减少MDSC的数量，因为其他直接钙调磷酸酶信号通路抑制剂具有相同的剂量依赖性作用。这些数据表明，增强MDSC可以减少环孢素A引起的心血管和肾脏毒性以及高血压。
The calcineurin inhibitor cyclosporine A suppresses the immune system but promotes hypertension, vascular dysfunction, and renal damage. Cyclosporine A decreases regulatory T cells and this contributes to the development of hypertension. However, cyclosporine A’s effects on another important regulatory immune cell subset, myeloid-derived suppressor cells (MDSCs), is unknown. We hypothesized that augmenting MDSCs would ameliorate the cyclosporine A-induced hypertension and vascular and renal injury and dysfunction and that cyclosporine A reduces MDSCs in mice. Daily interleukin-33 treatment, which increased MDSC levels, completely prevented cyclosporine A-induced hypertension and vascular and renal toxicity. Adoptive transfer of MDSCs from control mice into cyclosporine A-treated mice after hypertension was established dose-dependently reduced blood pressure and vascular and glomerular injury. Cyclosporine A treatment of aortas and kidneys isolated from control mice for 24 hours decreased relaxation responses and increased inflammation, respectively, and these effects were prevented by the presence of MDSCs. MDSCs also prevented the cyclosporine A-induced increase in fibronectin in microvascular and glomerular endothelial cells. Lastly, cyclosporine A dose-dependently reduced the number of MDSCs by inhibiting calcineurin and preventing cell proliferation, as other direct calcineurin signaling pathway inhibitors had the same dose-dependent effect. These data suggest that augmenting MDSCs can reduce the cardiovascular and renal toxicity and hypertension caused by cyclosporine A.