Key result
TREM2 deficiency attenuates hypoxia-induced pulmonary hypertension and vascular remodeling in mice.
Why the study?
The molecular regulators of pathological activation of myeloid-derived suppressor cells and macrophages in pulmonary hypertension remain poorly defined, including the role of TREM2.
Does TREM2 deficiency attenuate hypoxia-induced right ventricular dysfunction, pulmonary inflammation, and vascular remodeling in models of pulmonary hypertension?
Does TREM2 deficiency attenuate hypoxia-induced right ventricular dysfunction, pulmonary inflammation, and vascular remodeling in models of pulmonary hypertension?
TREM2 is a key driver of myeloid-driven immunosuppression and vascular remodeling in pulmonary arterial hypertension, highlighting it as a potential therapeutic target and biomarker.
TREM2 may represent a novel therapeutic target in PH; leaves open whether modulating it alters clinical outcomes.
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.
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Oliveira et al. (2026) studied Pulmonary hypertension (n=41). TREM2 deficiency and expression vs. Wild-type mice and healthy human controls was evaluated on Hypoxia-induced right ventricular systolic pressure increase, right ventricular dysfunction, pulmonary inflammation, and vascular remodeling. TREM2 deficiency attenuated hypoxia-induced pulmonary hypertension and vascular remodeling in mice, and TREM2 was significantly elevated in circulating MDSCs from PAH patients.
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