D108-14 A Distinct Neat1-High COPD Neutrophil Population Promotes Lung Tissue Injury

Abstract Rationale Chronic Obstructive Pulmonary Disease (COPD) is characterized by persistent neutrophilic inflammation, with neutrophil elastase and extracellular traps (NET) contributing to disease severity. Despite significant advances in understanding their role in COPD pathogenesis, direct preventative and therapeutic targeting of these cells has so far failed, underscoring the need to investigate molecular targeted interventions. In this study, we identify a unique disease specific population of neutrophils expressing long non-coding RNA NEAT1 (Nuclear Paraspeckle Assembly Transcript 1) as a key regulator of neutrophil hyperactivation and tissue injury, particularly in COPD patients. Methods We analyzed scRNA-seq of blood neutrophils from COPD patients. NEAT1 expression was validated in peripheral neutrophils from human COPD patients and cigarette smoke (CS)-exposed mice. The impact of NEAT1 silencing and STAT3 inhibition on NET formation, myeloperoxidase (MPO) / neutrophil elastase (NE) quantification, and reactive oxygen species (ROS) production were assessed. Functional neutrophil-driven tissue damage was evaluated using human and mice precision-cut lung slices. Results In a sub-population of neutrophils from COPD patients and CS-exposed mice NEAT1 was significantly upregulated. Mechanistically, STAT3-regulated NEAT1 was identified as a key driver, modulating the expression of the NADPH oxidase subunit gene NCF2 to enhance ROS production and promote NET formation. Inhibition of NEAT1 led to decreased expression of NCF2, ROS, MPO and NE, resulting in reduced NET formation. Ultimately, neutrophils lacking NEAT1 activity were found to protect lung tissue from injury. Conclusion A high NEAT1 subpopulation of neutrophils is the central driver of NETosis and neutrophil-mediated lung damage in COPD. Targeting NEAT1 may offer a novel therapeutic strategy to reduce inflammation and tissue injury in COPD patients. This abstract is funded by: German Center for Lung Research (DZL)