Treatment With Endothelin-A Receptor Antagonist BQ123 Attenuates Acute Inflammation in Mice Through T-Cell-Dependent Polymorphonuclear Myeloid-Derived Suppressor Cell Activation.
Treatment With Endothelin-A Receptor Antagonist BQ123 Attenuates Acute Inflammation in Mice Through T-Cell-Dependent Polymorphonuclear Myeloid-Derived Suppressor Cell Activation.
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DOI：
10.3389/fimmu.2021.641874
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发表时间：
2021
影响因子：
7.3
通讯作者：
He Y
中科院分区：
文献类型：
--
作者：
Chen Z;Zhang X;Lv S;Xing Z;Shi M;Li X;Chen M;Zuo S;Tao Y;Xiao G;Liu J;He Y
内皮素A受体拮抗剂BQ123是治疗高血压和肥胖性心肌病的有效药物。然而，BQ123在控制急性炎症性疾病中的作用及其潜在机制尚不清楚。在这里，我们发现BQ123激活了小鼠中的多形核细胞骨髓源性抑制细胞（PMN-MDSC），并且IL 13/STAT6/Arg1信号通路参与了这一过程。重要的是，用BQ123治疗和BQ123诱导的PMN-MDSC（BQ123-MDSC）的转移都有效缓解小鼠中的炎症，包括葡聚糖硫酸钠（DSS）诱导的结肠炎、木瓜蛋白酶诱导的肺炎和伴刀豆球蛋白A（ConA）诱导的肝炎。治疗效果是通过减轻与PMN-MDSC在结肠、肺和肝脏中积累相关的炎症来介导的。然而，同时注射Gr1激动性抗体与BQ123诱导的PMN-MDSC加重了观察到的急性炎症。有趣的是，在给予BQ123-MDSC的Rag2敲除小鼠中没有观察到炎症缓解，但与CD3 + T细胞共注射显著缓解了急性炎症。总之，BQ123诱导的PMN-MDSC以T细胞依赖性方式减轻急性炎症，提供了预防急性炎症发生的新的潜在策略。
The endothelin-A receptor antagonist BQ123 is an effective treatment agent for hypertension and obese cardiomyopathy. However, the role of BQ123 in controlling acute inflammatory diseases and its underlying mechanisms are not well understood. Here, we showed that BQ123 activated polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in mice and that the IL13/STAT6/Arg1 signaling pathway is involved in this process. Importantly, both treatment with BQ123 and the transfer of BQ123-induced PMN-MDSCs (BQ123-MDSCs) were effective in relieving inflammation, including dextran sulfate sodium (DSS)-induced colitis, papain-induced pneumonia, and concanavalin A (ConA)-induced hepatitis, in mice. The treatment effects were mediated by the attenuation of the inflammation associated with the accumulation of PMN-MDSCs in the colon, lung, and liver. However, concurrent injection of Gr1 agonistic antibody with BQ123 induced PMN-MDSC aggravated the observed acute inflammation. Interestingly, no remission of inflammation was observed in Rag2 knockout mice administered BQ123-MDSCs, but co-injection with CD3+ T cells significantly relieved acute inflammation. In summary, BQ123-induced PMN-MDSCs attenuated acute inflammation in a T cell-dependent manner, providing a novel potential strategy to prevent the occurrence of acute inflammation.
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