bioRxiv : the preprint server for biology · 2026
TREM2 Orchestrates Myeloid Cell Programming and Immune Dysregulation in Pulmonary Hypertension.
СтатьяПрепринтНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Oliveira Aline C, da Silva Filipe, Zhang Yutao, Alves Matthew D, Pham Ann T, Harris Charlotte, Khanfar Sultan, Abdelnor Rafael, Alvarez-Castanon Jimena, Phillips Caroline, Hall Mia T, Fu Chunhua, Virk Shiza T, Ray Katherine E, Chen Li, de Kloet Annette, Krause Eric, Bryant Andrew J
Аннотация
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.
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.