Wu Xiaowen, Pan Guanxing, Chang Lin, Liu Qian, Liu Yangyang, Zhang Wei, Guo Yifan, Zhang Ge, Zhong Haoxuan, Qi Zhiyong, Zhang Jianjun, Xue Ruyi, Chen She, Hu Hu, Dong Jianzeng, Zhang Si, Ding Zhongren
School of Pharmacy Tianjin Medical University Tianjin China.
Department of Biochemistry and Molecular Biology School of Basic Medical Sciences, Fudan University Shanghai China.
J Am Heart Assoc. 2025 Jul;14(13):e041220. doi: 10.1161/JAHA.124.041220. Epub 2025 Jun 23.
Coronary artery disease is characterized by chronic immune-inflammation, excessive endoplasmic reticulum (ER) stress, and platelet hyperactivity; however, whether there is a signaling hub linking these events remains unclear. Here, we identified that TREM2 (triggering receptor expressed on myeloid cells 2), an important pattern recognition receptor of the innate immune system, may serve as one such hub.
TREM2 expression and ER stress were assessed in platelets. Transcriptional repression of TREM2 by excessive ER stress was evaluated using luciferase assay, chromatin immunoprecipitation, and electrophoretic mobility shift assay. The effects of TREM2 deficiency on platelet function, mouse FeCl-induced mesenteric arterial thrombosis, and myocardial infarction were explored. A TREM2-activating antibody was also evaluated for its antiplatelet, antithrombotic, and cardioprotective potential against myocardial infarction.
We found that platelets express TREM2, and its expression is reduced in platelets from patients with coronary artery disease. Excessive ER stress downregulated TREM2 through the CHOP (C/EBP-homologous protein)-C/EBPα axis. TREM2 deficiency enhanced platelet activation in response to adenosine diphosphate, collagen, and CRP (collagen-related peptide). TREM2 deficiency exacerbated mouse mesenteric arterial thrombosis and aggravated experimental myocardial infarction. Furthermore, a TREM2-activating antibody inhibited platelet activation, reduced thrombosis, and alleviated experimental myocardial infarction. Mechanistically, the TREM2/DAP12 (DNAX activating protein of 12 kDa)/SHIP1 (Src homology 2 domain-containing inositol 5-phosphatase) axis negatively regulated platelet activation through reducing phosphatidylinositol (3,4,5)-trisphosphate levels and inhibiting Akt phosphorylation. Sphingosine-1-phosphate was identified as a physiological TREM2 agonist.
TREM2 integrates ER stress, immune inflammation, and platelet function. ER stress-induced TREM2 downregulation contributes to platelet hyperactivation in coronary artery disease, suggesting TREM2 activation as a novel therapeutic target.
冠状动脉疾病的特征是慢性免疫炎症、内质网（ER）应激过度和血小板活性过高；然而，是否存在连接这些事件的信号枢纽仍不清楚。在此，我们发现髓系细胞触发受体2（TREM2），一种先天性免疫系统的重要模式识别受体，可能充当这样一个枢纽。
评估血小板中TREM2的表达和内质网应激。使用荧光素酶测定、染色质免疫沉淀和电泳迁移率变动分析评估内质网应激过度对TREM2的转录抑制作用。探讨TREM2缺陷对血小板功能、小鼠FeCl诱导的肠系膜动脉血栓形成和心肌梗死的影响。还评估了一种TREM2激活抗体对心肌梗死的抗血小板、抗血栓形成和心脏保护潜力。
我们发现血小板表达TREM2，且在冠状动脉疾病患者的血小板中其表达降低。内质网应激过度通过CHOP（C/EBP同源蛋白）-C/EBPα轴下调TREM2。TREM2缺陷增强了血小板对二磷酸腺苷、胶原和CRP（胶原相关肽）的反应性激活。TREM2缺陷加剧了小鼠肠系膜动脉血栓形成并加重了实验性心肌梗死。此外，一种TREM2激活抗体抑制血小板激活、减少血栓形成并减轻实验性心肌梗死。机制上，TREM2/DAP12（12 kDa的DNAX激活蛋白）/SHIP1（含Src同源2结构域的肌醇5-磷酸酶）轴通过降低磷脂酰肌醇（3,4,5）-三磷酸水平和抑制Akt磷酸化来负向调节血小板激活。鞘氨醇-1-磷酸被鉴定为一种生理性TREM2激动剂。
TREM2整合内质网应激、免疫炎症和血小板功能。内质网应激诱导的TREM2下调促成了冠状动脉疾病中的血小板过度激活，提示TREM2激活作为一个新的治疗靶点。
