ER stress-induced TREM2 downregulation exacerbates platelet activation and myocardial infarction in patients with coronary artery disease

Xiaowen Wu, Guanxing Pan, Lin Chang, Yulong Zhang, Yangyang Liu, Wei Zhang, Yifan Guo, Ge Zhang, Haoxuan Zhong, Zhiyong Qi, Jianjun Zhang, Ruyi Xue, She Chen, Hu Hu, Jianzeng Dong, Si Zhang, Zhongren Ding
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Abstract

Coronary artery disease (CAD) is characterized by the 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 triggering receptor expressed on myeloid cells 2 (TREM2), an important pattern recognition receptor of the innate immune system, may serve as one such hub. We found that platelets expressed TREM2 and platelets from CAD patients had decreased TREM2 expression compared to healthy subjects. Decreased TREM2 is associated with platelet hyperactivity in CAD patients. This decrease could be due to excessive ER stress, which downregulated TREM2 through the CHOP-C/EBPα axis. Loss of TREM2 not only enhanced platelet activation in response to ADP, collagen, and collagen-related peptide (CRP), but also amplified the platelet inflammatory response. Loss of TREM2 exacerbated mouse mesenteric arterial thrombosis and aggravated experimental myocardial infarction (MI). Moreover, a TREM2-activating antibody inhibited platelet activation, alleviated arterial thrombosis and pulmonary embolism. In addition, TREM2-activating antibody exhibited cardioprotective roles against experimental MI and reduced the inflammatory burden. Mechanistically, TREM2/DAP12/SHIP1 axis negatively regulated platelet activation through reducing PIP3 levels and inhibiting Akt phosphorylation. We also provided evidence supporting sphingosine-1-phospage (S1P) as a physiological agonist of TREM2. In summary, we find that TREM2 connects chronic immune-inflammation, excessive ER stress, and platelet hyperactivity in CAD patients. Downregulating TREM2 by ER stress exacerbates platelet activation and amplifies inflammation response in patients with CAD. TREM2-activating antibodies may have therapeutic potential for CAD patients.
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ER应激诱导的TREM2下调会加剧冠心病患者的血小板活化和心肌梗死
冠状动脉疾病(CAD)的特点是慢性免疫炎症、过度的内质网(ER)应激和血小板活性亢进;然而,是否有一个信号枢纽将这些事件联系起来仍不清楚。在这里,我们发现髓系细胞上表达的触发受体 2(TREM2)--一种先天性免疫系统的重要模式识别受体--可能就是这样一个枢纽。我们发现血小板表达 TREM2,与健康人相比,CAD 患者血小板的 TREM2 表达减少。TREM2 的减少与 CAD 患者血小板的过度活跃有关。这种减少可能是由于过度的ER应激通过CHOP-C/EBPα轴下调了TREM2。TREM2的缺失不仅增强了血小板对ADP、胶原蛋白和胶原蛋白相关肽(CRP)的活化反应,还扩大了血小板的炎症反应。失去 TREM2 会加剧小鼠肠系膜动脉血栓形成,并加重实验性心肌梗塞(MI)。此外,TREM2 激活抗体可抑制血小板活化,缓解动脉血栓和肺栓塞。此外,TREM2-激活抗体对实验性心肌梗死具有心脏保护作用,并能减轻炎症负担。从机制上讲,TREM2/DAP12/SHIP1 轴通过降低 PIP3 水平和抑制 Akt 磷酸化负向调节血小板活化。我们还提供了支持鞘磷脂-1-磷酸(S1P)作为 TREM2 生理激动剂的证据。总之,我们发现 TREM2 将慢性免疫炎症、过度的 ER 应激和 CAD 患者的血小板过度活跃联系在一起。通过ER应激下调TREM2会加剧CAD患者的血小板活化和炎症反应。激活 TREM2 的抗体可能对 CAD 患者有治疗潜力。
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