{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T23:05:21Z","timestamp":1789599921999,"version":"build-2803163510"},"reference-count":54,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2026,8,28]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Chronic inflammation is a key driver of atherosclerotic cardiovascular disease. Notably, anti-inflammatory therapies have demonstrated efficacy in reducing cardiac events. We previously reported that TREM2 (triggering receptor expressed on myeloid cells 2) promotes foam cell formation in atherosclerosis. Elevated levels of sTREM2 (soluble TREM2) have been observed in the plasma of patients with atherosclerosis. This study sought to investigate the pathological role of sTREM2 in the progression of atherosclerosis, elucidate its underlying mechanistic pathways, and propose potential targeted therapeutic interventions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      Plasma sTREM2 levels were measured in patients with carotid atherosclerosis and in apolipoprotein E\u2013deficient (\n                      <jats:italic toggle=\"yes\">Apoe<\/jats:italic>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      ) mice. To study the functional role of sTREM2, we administered recombinant sTREM2 to\n                      <jats:italic toggle=\"yes\">Apoe<\/jats:italic>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      mice and used macrophage-specific\n                      <jats:italic toggle=\"yes\">Hsp90ab1<\/jats:italic>\n                      knockout mice (\n                      <jats:italic toggle=\"yes\">Hsp90ab1<\/jats:italic>\n                      <jats:sup>Mac-KO<\/jats:sup>\n                      ). Mechanistic pathways were investigated using immunoprecipitation-mass spectrometry, and surface plasmon resonance imaging was used to identify sTREM2 antagonists.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Plasma sTREM2 levels correlated with atherosclerotic burden in both humans and mice. Exogenous sTREM2 administration exacerbated plaque progression in\n                      <jats:italic toggle=\"yes\">Apoe<\/jats:italic>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      mice, an effect abolished in\n                      <jats:italic toggle=\"yes\">Hsp90ab1<\/jats:italic>\n                      <jats:sup>Mac-KO<\/jats:sup>\n                      mice. Mechanistically, sTREM2 binds to HSP90\u03b2 (heat shock protein 90 beta), enhancing its interaction with the IKKs (I\u03baB kinase complex), thereby activating the I\u03baB\u03b1 (inhibitor of nuclear factor-\u03baB)\/NF-\u03baB (nuclear factor-\u03baB) P65 pathway. This activation potentiates monocyte adhesion and chemotaxis and enhances macrophage inflammatory activation signatures in atherosclerotic lesions\u2014effects that were reversed on myeloid-specific\n                      <jats:italic toggle=\"yes\">Hsp90ab1<\/jats:italic>\n                      deletion. Additionally, we identified 3-bromopyruvate as a small-molecule antagonist that selectively disrupts the sTREM2\/HSP90\u03b2 interaction and attenuates atherosclerosis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>sTREM2 promotes proatherogenic myeloid recruitment and macrophage inflammatory activation via HSP90\u03b2-dependent NF-\u03baB activation. Genetic and pharmacological approaches establish the sTREM2\/HSP90\u03b2 axis as a druggable target, with 3-bromopyruvate demonstrating translational potential for atherosclerosis therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.125.327491","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T09:00:17Z","timestamp":1785315617000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Soluble TREM2 Drives Atherosclerosis via HSP90\u03b2-Dependent Myeloid Inflammation"],"prefix":"10.1161","volume":"139","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9591-7484","authenticated-orcid":true,"given":"Xiaoqing","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Neurology (X.G., M.Q., S.W., J.C., D.J., Y.F., Jiangnan Yu, L.M.), Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 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University of Science and Technology, Wuhan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5622-1564","authenticated-orcid":true,"given":"Yuhang","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Neurology (X.G., M.Q., S.W., J.C., D.J., Y.F., Jiangnan Yu, L.M.), Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangnan","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Neurology (X.G., M.Q., S.W., J.C., D.J., Y.F., Jiangnan Yu, L.M.), Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4379-8748","authenticated-orcid":true,"given":"Xiaojun","family":"Xu","sequence":"additional","affiliation":[{"name":"Center for 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