Sex-dependent transcriptional and epigenetic regulation of neutrophil inflammatory programs in COPD.

Introduction: Sex differences strongly influence immune responses and susceptibility to inflammatory diseases, yet how biological sex shapes immune regulatory mechanisms in chronic obstructive pulmonary disease (COPD) remains poorly understood. Neutrophils are key drivers of COPD pathogenesis, but whether biological sex shapes their inflammatory programming has not been systematically investigated. Methods: Here we integrated transcriptomic and epigenomic profiling of circulating neutrophils from male and female COPD patients to define sex-dependent regulatory programs in innate immune cells. Results: Unsupervised analyses revealed that sex represents a major source of transcriptional variation in neutrophils. Although COPD induced a shared disease-associated transcriptional signature in both sexes, the magnitude and functional orientation of this response differed markedly. Male COPD neutrophils displayed robust enrichment of interferon signaling, cytokine-mediated pathways, and inflammatory networks. These transcriptional changes in male were accompanied by widespread H3K27ac enrichment at promoters and enhancers of inflammatory loci, and by elevated plasma levels of CXCL8, TNF-α, IFN-α, IFN-γ, and VEGF inflammatory mediators. In contrast, female neutrophils preferentially exhibited transcriptional programs related to autophagy and vesicle-mediated processes. Discussion: These findings define a model in which COPD elicits a shared neutrophil transcriptional framework that is amplified through sex-specific epigenetic and inflammatory feedback. This male-biased inflammatory reprogramming provides a mechanistic basis for sex differences in COPD immunopathology and highlights the importance of incorporating sex as a biological variable in the development of precision therapies for chronic inflammatory disease.