Ruoxuan Jiang, Liuyi Li, Yuhang Luo, Wen Wang, Xiaoya Zeng, Cheng Qian, Chen Gong, Jianlong Shen
Second Affiliated Hospital of Anhui Medical University. First Affiliated Hospital of Anhui Medical University.
China
International Immunopharmacology
Int Immunopharmacol 2026;
DOI: 10.1016/j.intimp.2026.116394
Abstract
Pulmonary arterial hypertension (PAH) is a fatal disease marked by pulmonary vascular remodeling. Although endothelial dysfunction and immune cell infiltration are central to its pathogenesis, the specific signaling mechanisms linking these elements remain unclear. This study investigates a novel pathway whereby endothelial cell-derived GM-CSF drives macrophage-dependent inflammation via the CCL2/CCR2 axis, ultimately promoting PAH progression through NLRP3 inflammasome activation. PAH mouse model was established using a high-fat diet (HFD) combined with L-NAME. Comprehensive in vivo assessments included echocardiography to evaluate cardiac function, Masson’s Trichrome to measure vascular remodeling. In vitro, a co-culture system of mouse pulmonary arterial endothelial cells (MPAECs) and bone marrow-derived macrophages (BMDMs) was used, with palmitic acid (PA) stimulation to mimic PAH conditions. Key interventions involved administering a GM-CSF neutralizing antibody, depleting macrophages with clodronate liposomes, and utilizing Ccr2-/- mice. PAH mice exhibited significant pulmonary arterial wall thickening, right heart dysfunction, and increased lung wet-to-dry weight ratio. This was accompanied by early and sustained upregulation of GM-CSF and CCL2 in lung tissues, extensive infiltration of CCR2+ macrophages, and activation of the NLRP3 inflammasome cascade. In vitro, PA-stimulated MPAECs released GM-CSF, which promoted macrophage migration and CCL2 secretion, induced a pro-inflammatory M1 phenotype, and activated the NLRP3 pathway. Crucially, in vivo therapeutic interventions demonstrated that neutralizing GM-CSF, depleting macrophages, or knocking out Ccr2 all significantly alleviated PAH pathology. This study confirms that endothelial cell-derived GM-CSF promotes macrophage-NLRP3 inflammasome via the CCL2/CCR2 axis, thereby driving the progression of PAH. This axis may represent a promising therapeutic target for PAH.
Category
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Class I. Pulmonary Hypertension Associated with Inflammation
Pulmonary Vascular Pathology
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
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Free PDF File or Full Text Article Available Through PubMed or DOI: Yes