Innate immune reprogramming in circulating neutrophils of COPD patients.

Abstract

BACKGROUND Chronic obstructive pulmonary disease (COPD) involves both local and systemic neutrophilic inflammation, with dysregulation in blood neutrophil numbers, frequencies, and functions. OBJECTIVE To characterize the transcriptional and epigenetic profiles of circulating neutrophils in COPD patients and explore correlations with neutrophil dysfunction and clinical disease parameters. METHODS Circulating neutrophils of COPD patients and control donors were subjected to RNA-sequencing (RNA-seq) and genome-wide analysis of histone 3 lysine 4 trimethylation (H3K4me3) by Chromatin Immunoprecipitation coupled with sequencing (ChIP-seq). Neutrophils' activation was assessed by cytofluorimetric analysis, O2- release and C. albicans phagocytosis assays. RESULTS RNA-seq and ChIP-seq analysis of H3K4me3 revealed a poised state in genes involved in innate immune activation, resembling the phenotype observed in neutrophils from BCG-vaccinated individuals, referred to as "trained", that is marked by weak or no expression under resting conditions but ready to be expressed at higher levels upon stimulation. The epigenetic signature identified in neutrophils from BCG-vaccinated subjects was enriched in COPD neutrophils. In particular, and consistent with what has been described in "trained" neutrophils, COPD neutrophils exhibited transcriptional reprogramming of metabolically relevant genes. Functionally, COPD neutrophils produced higher CXCL8 and IL-1β levels, released more O2-, and displayed greater phagocytic activity upon in vitro stimulation. CONCLUSION These findings suggest that COPD neutrophils undergo epigenetic, transcriptomic, and metabolic reprogramming, which enhances their responsiveness and aligns with the phenotype of neutrophils previously identified as "trained", offering mechanistic insight into the functional dysregulation observed in COPD.