Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, 371-8512, Japan.
Sci Rep. 2017 Aug 10;7(1):7812. doi: 10.1038/s41598-017-07573-2.
Myocardial infarction (MI) is an ischaemic heart condition caused by the occlusion of coronary arteries. Following MI, lactic acid from anaerobic glycolysis increases and infiltrating immune cells produce severe inflammation, which leads to acidosis in the ischaemic heart. However, the physiological implication of this pH reduction remains largely unknown. T-cell death-associated gene 8 (TDAG8) is a proton-sensing G protein-coupled receptor found on cardiac macrophages that recognise increases in extracellular protons. We demonstrated that TDAG8 negatively regulates the transcription of the chemokine Ccl20. The infarcted hearts of TDAG8 KO mice showed an increase in CCL20 expression and the number of infiltrating IL-17A-producing γδT cells that express CCR6, a receptor for CCL20. Accordingly, excessive IL-17A production, which is linked to the functional deterioration after MI, was observed in MI-operated TDAG8 KO mice. The survival rate and cardiac function significantly decreased in TDAG8 KO mice compared with those in wild-type mice after MI. Thus, our results suggest that TDAG8 is a key regulator of MI and a potential therapeutic target.
心肌梗死（MI）是由冠状动脉阻塞引起的缺血性心脏病。MI 后，无氧糖酵解产生的乳酸增加，浸润的免疫细胞产生严重的炎症，导致缺血性心脏酸中毒。然而，这种 pH 值降低的生理意义在很大程度上尚不清楚。T 细胞死亡相关基因 8（TDAG8）是一种存在于心脏巨噬细胞上的质子感应 G 蛋白偶联受体，可识别细胞外质子的增加。我们证明 TDAG8 负调控趋化因子 Ccl20 的转录。TDAG8 KO 小鼠的梗死心脏中 CCL20 的表达增加，并且表达 CCL20 的受体 CCR6 的浸润的产生 IL-17A 的 γδT 细胞的数量增加。因此，在 MI 手术后的 TDAG8 KO 小鼠中观察到与 MI 后功能恶化相关的过度 IL-17A 产生。与野生型小鼠相比，MI 后 TDAG8 KO 小鼠的存活率和心功能显著降低。因此，我们的研究结果表明 TDAG8 是 MI 的关键调节剂和潜在的治疗靶点。
