{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T04:29:15Z","timestamp":1788496155301,"version":"build-2803163510"},"reference-count":71,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"13","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:sec id=\"jah311104-sec-0001\" xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Coronary artery disease is characterized by chronic immune\u2010inflammation, 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"jah311104-sec-0002\" xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      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\n                      <jats:sub>3<\/jats:sub>\n                      \u2010induced mesenteric arterial thrombosis, and myocardial infarction were explored. A TREM2\u2010activating antibody was also evaluated for its antiplatelet, antithrombotic, and cardioprotective potential against myocardial infarction.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"jah311104-sec-0003\" xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">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\u2010homologous protein)\u2010C\/EBP\u03b1 axis. TREM2 deficiency enhanced platelet activation in response to adenosine diphosphate, collagen, and CRP (collagen\u2010related peptide). TREM2 deficiency exacerbated mouse mesenteric arterial thrombosis and aggravated experimental myocardial infarction. Furthermore, a TREM2\u2010activating 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\u2010containing inositol 5\u2010phosphatase) axis negatively regulated platelet activation through reducing phosphatidylinositol (3,4,5)\u2010trisphosphate levels and inhibiting Akt phosphorylation. Sphingosine\u20101\u2010phosphate was identified as a physiological TREM2 agonist.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"jah311104-sec-0004\" xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">TREM2 integrates ER stress, immune inflammation, and platelet function. ER stress\u2010induced TREM2 downregulation contributes to platelet hyperactivation in coronary artery disease, suggesting TREM2 activation as a novel therapeutic target.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.124.041220","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T00:03:46Z","timestamp":1750723426000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["Endoplasmic Reticulum Stress\u2010Induced triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Downregulation Exacerbates Platelet Activation and Myocardial Infarction in Patients With Coronary Artery Disease"],"prefix":"10.1161","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4434-7319","authenticated-orcid":false,"given":"Xiaowen","family":"Wu","sequence":"first","affiliation":[{"name":"Tianjin Medical University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanxing","family":"Pan","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Fudan University","place":["Shanghai, China"]},{"name":"The First Affiliated Hospital of Fujian Medical University","place":["Fuzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1878-6155","authenticated-orcid":false,"given":"Lin","family":"Chang","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Liu","sequence":"additional","affiliation":[{"name":"Tianjin Medical University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8296-7095","authenticated-orcid":false,"given":"Yangyang","family":"Liu","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0548-6348","authenticated-orcid":false,"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4675-9368","authenticated-orcid":false,"given":"Yifan","family":"Guo","sequence":"additional","affiliation":[{"name":"Zhongshan Hospital, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ge","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5038-299X","authenticated-orcid":false,"given":"Haoxuan","family":"Zhong","sequence":"additional","affiliation":[{"name":"Huashan Hospital, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5720-4061","authenticated-orcid":false,"given":"Zhiyong","family":"Qi","sequence":"additional","affiliation":[{"name":"Zhongshan Hospital, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9689-9898","authenticated-orcid":false,"given":"Jianjun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shanghai Pudong Hospital, Fudan University Pudong Medical Center","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruyi","family":"Xue","sequence":"additional","affiliation":[{"name":"Fudan University Zhongshan Hospital","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4077-1649","authenticated-orcid":false,"given":"She","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0009-8218","authenticated-orcid":false,"given":"Hu","family":"Hu","sequence":"additional","affiliation":[{"name":"Zhejiang University School of Medicine","place":["Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8001-7010","authenticated-orcid":false,"given":"Jianzeng","family":"Dong","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5682-4995","authenticated-orcid":false,"given":"Si","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9487-4865","authenticated-orcid":false,"given":"Zhongren","family":"Ding","sequence":"additional","affiliation":[{"name":"Tianjin Medical University","place":["Tianjin, China"]},{"name":"School of Basic Medical Sciences, Fudan University","place":["Shanghai, China"]},{"name":"General Hospital of Tianjin Medical University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(24)00367-2"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aax0481"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra071014"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2018.02.013"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2020.05.004"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.114.013743"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.112.274241"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.117.311069"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2016.07.004"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20022220"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20041611"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.05.003"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.05.054"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.120.046290"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.116.026995"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00277-004-0926-z"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-020-01028-4"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.116.023711"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.118.034600"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.223925"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3284"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1111\/jth.12362"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.117.309751"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.2337\/db18-0981"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-05-433730"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000137836.95625.D4"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.08.009"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.2337\/db20-0092"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.6.3.439"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.227819"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.106.682054"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2017.182972"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-09-110437"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1111\/jth.13578"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-03-773614"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2019.232488"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.117.310795"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.118.033942"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-019-02817-1"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0002-9343(03)00329-2"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI83024"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.115.015656"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/0033-0620(87)90004-1"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.117.309856"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn.2016.7"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1160\/TH17-03-0156"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.2147\/RRBC.S58057"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2000500"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1111\/jth.13302"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M400746200"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-11-188516"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20030581"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1160\/TH16-02-0096"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0902844"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1002\/stem.1902"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2021.10.012"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2014.08.013"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2011.04194.x"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-38069-5"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.001848"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.112.255281"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0009746"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2009.03.003"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.20391"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V110.11.3630.3630"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1586\/ehm.09.75"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.117.312509"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1038\/s44161-024-00429-9"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.07.013"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.07.023"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-022-01240-0"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.124.041220","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T11:57:48Z","timestamp":1753876668000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.124.041220"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7]]},"references-count":71,"journal-issue":{"issue":"13","published-print":{"date-parts":[[2025,7]]}},"alternative-id":["10.1161\/JAHA.124.041220"],"URL":"https:\/\/doi.org\/10.1161\/jaha.124.041220","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7]]},"assertion":[{"value":"2025-01-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-15","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e041220"}}