TREM2 Orchestrates Myeloid Cell Programming and Immune Dysregulation in Pulmonary Hypertension
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…
Pulmonary hypertension (PH) is a life-threatening condition marked by abnormal expansion of the pulmonary arteries, inflammation, and immune dysregulation. Myeloid-derived suppressor cells (MDSCs) and macrophages play a significant role in the progression of pulmonary arterial hypertension (PAH), but the specific molecules controlling their harmful activation are still unclear.
TREM2, an immunomodulatory receptor, influences myeloid cell metabolism, survival, and immunosuppressive functions, yet its involvement in PH has not been studied.
Researchers used single-cell RNA sequencing to examine TREM2 expression in various cell types within human pulmonary arteries from patients with PH (n=3) and healthy individuals (n=3). They also subjected wild-type (WT) and global TREM2 knockout (TREM2 KO) mice to chronic hypoxia (10% FiO2 for 28 days) to observe the effects on hemodynamic, histological, flow cytometric, and ex vivo functional parameters.
TREM2 levels were measured in circulating MDSCs from PH patients (n=22) and healthy subjects (n=13) using flow cytometry.
The results revealed that TREM2 was highly prevalent in monocyte/macrophage populations in PH pulmonary arteries, and TREM2-positive immune cells presented a transcriptional shift towards downregulating chemotaxis programs and upregulating antigen processing and MHC II presentation pathways. TREM2 deficiency notably reduced hypoxia-induced right ventricular hypertrophy, right ventricular dysfunction, pulmonary inflammation, and vascular remodeling.
Moreover, MDSCs from TREM2 KO mice showed significantly less suppression of CD4+ and CD8+ T cell proliferation compared to WT mice.
TREM2 levels were significantly higher in the circulating MDSCs of PH patients than in healthy controls, and a directional correlation was observed between TREM2 levels and hemodynamic severity. The study concludes that TREM2 is a crucial regulator of myeloid-driven immunosuppression and vascular remodeling in PAH, suggesting that it could be a potential therapeutic target and biomarker for the disease.
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