{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T13:01:07Z","timestamp":1790686867031,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,24]]},"group-title":"Immunology","reference-count":49,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,24]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Background: Pulmonary hypertension (PH) is a progressive and fatal disease characterized by pulmonary vascular remodeling, inflammation, and immune dysregulation. Myeloid-derived suppressor cells (MDSCs) and macrophages contribute to PAH pathobiology; however, the molecular regulators of their pathological activation remain poorly defined. The triggering receptor expressed on myeloid cells 2 (TREM2) is an immunomodulatory receptor that shapes myeloid cell metabolism, survival, and immunosuppressive function, yet its role in PAH has not been investigated. Methods: Single-cell RNA sequencing (scRNA-seq) data from human pulmonary artery tissue (GSE210248; n=3 PAH, n=3 donors) were analyzed to characterize TREM2 expression across cell populations. Wild-type (WT) and global TREM2 knockout (TREM2 KO) mice were exposed to chronic hypoxia (10% FiO2, 28 days). Hemodynamic, histological, flow cytometric, and ex vivo functional assessments were performed. TREM2 protein expression was measured by flow cytometry in circulating MDSCs from PAH patients (n=22) and healthy controls (n=13). Results: TREM2 was markedly enriched in monocyte\/macrophage (mono\/macs) populations in PAH pulmonary arteries, with co-upregulation of APOE, GPNMB, and CSF1R. TREM2-high immune cells exhibited transcriptional downregulation of chemotaxis programs and upregulation of antigen processing and MHC II presentation pathways. TREM2 deficiency significantly attenuated hypoxia-induced RVSP increase, right ventricular dysfunction, pulmonary inflammation, and vascular remodeling. TREM2 KO mice showed blunted mTOR\/p-S6 activation in bone marrow myeloid populations and MDSCs from TREM2 KO mice exerted significantly less suppression of CD4+ and CD8+ T cell proliferation. TREM2 KO mice tended to preserve bone marrow CD4+ T cell proportions and significant upregulation of CD62L on T cells under hypoxia. TREM2 was significantly elevated in circulating MDSCs from PAH patients and showed a directional association with hemodynamic severity. Conclusions: TREM2 is a novel regulator of myeloid-driven immunosuppression and vascular remodeling in PAH and warrants investigation as a therapeutic target and biomarker.<\/jats:p>","DOI":"10.64898\/2026.09.18.752808","type":"posted-content","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:40:28Z","timestamp":1790296828000},"source":"Crossref","is-referenced-by-count":0,"title":["TREM2 Orchestrates Myeloid Cell Programming and Immune Dysregulation in Pulmonary Hypertension"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5357-4767","authenticated-orcid":false,"given":"Aline C.","family":"Oliveira","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Therapeutics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filipe","family":"da Silva","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, College of Medicine, University of Florida, Gainesville, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew D.","family":"Alves","sequence":"additional","affiliation":[{"name":"Department of Medicine, Divisions of Critical Care, Pulmonary & Sleep Medicine, College of Medicine, University of Florida, Gainesville, Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4413-3211","authenticated-orcid":false,"given":"Ann T.","family":"Pham","sequence":"additional","affiliation":[{"name":"Department of Medicine, Divisions of Critical Care, Pulmonary & Sleep Medicine, College of Medicine, University of Florida, Gainesville, Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Harris","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sultan","family":"Khanfar","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Abdelnor","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimena","family":"Alvarez-Castanon","sequence":"additional","affiliation":[{"name":"Department of Medicine, Divisions of Critical Care, Pulmonary & Sleep Medicine, College of Medicine, University of Florida, Gainesville, 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