CD177 + Neutrophils Promote Endothelial Senescence Through Extracellular Traps in Behçet Disease

Objective To investigate CD177 + PMN dysregulation on endothelial cells in Behçet disease (BD), a chronic systemic vasculitis characterized by polymorphonuclear neutrophil (PMN) activation and endothelial dysfunction. Methods We reanalyzed BD PMN RNA‐sequencing data and quantified CD177 + PMN in BD peripheral (n = 38) and vascular tissue. We then analyzed BD and healthy control CD177 + PMN using RNA sequencing (n = 7) and measured neutrophil extracellular trap (NET) production, which were used to stimulate vascular endothelial cells (VECs) for RNA‐sequencing analysis. Differentially expressed proteins in NETs were determined by mass spectrometry. Senescence, senescence‐associated secretory phenotype (SASP), and PMN chemotaxis of VECs treated with BD CD177 + PMN‐derived NETs were assessed. Results Transcriptome analysis revealed BD PMN overexpressed CD177. CD177 + PMN subset was expanded in active and severe systemic BD and accumulated in BD aortic walls. Enhanced NETosis and oxidative phosphorylation in BD CD177 + PMN were noted in RNA sequencing, which were confirmed in both resting and activated BD CD177 + PMN. BD CD177 + PMN‐derived NETs promoted senescence, SASP, and PMN chemotaxis in VECs using RNA‐sequencing analysis, which were validated by up‐regulated IL‐6, CXCL8, ICAM‐1, p21, SA‐β‐gal, and cell proliferation arrest. Mass spectrometry identified that BD CD177 + PMN‐derived NETs contained more histone 3.1 (H3.1). H3.1 induced senescence, SASP, and PMN chemotaxis in VECs via Toll‐like receptor 4 signaling, which was attenuated by senolytics. Conclusion Increased CD177 + PMN in patients with BD promotes senescence and SASP in VECs through secreting H3.1‐enriched NETs, which recruit PMN and collectively contribute to vasculitis in BD.