Work

PROK2 defines a pathogenic neutrophil subset and serves as a clinical indicator of neutrophilic inflammation in COPD

Year: 2026

Type: article

Abstract: PURPOSE: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease with progressive airflow limitation. However, the key pathogenic immune cell subset remains unknown. METHODS: A cigarette smoke-induced COPD mouse model was established. The composition, phenotypic state, and intercellular communication of immune cells in the lungs were characterized using scRNA-seq and flow cytometry. PROK2 and inflammatory mediators were validated by multiplex immunofluorescence and by ELISA in mice and patients with COPD. RESULTS: Chronic cigarette smoke (CS) exposure caused COPD and neutrophil-dominant immune remodeling. Notably, a neutrophil subset, PROK2+ neutrophils (Neu-PROK2), became the dominant neutrophil population, and exhibited elevated expression of matrix metalloproteinases (MMPs), NADPH oxidase components, and neutrophil extracellular traps-related genes, contributing to tissue injury under CS. Multiplex immunofluorescence also revealed PROK2 was primarily localized in alveolar LY6G⁺ neutrophils in CS lungs. Furthermore, Neu-PROK2 comprised an intermediate Ltf lo reservoir and a terminal hyperinflammatory Ltf hi state, forming a CS-driven continuum that progresses from Neu-PROK2 Ltf lo toward Ltf hi, with FOSL1 acting as an upstream driver. Importantly, Serum PROK2 was elevated in stable COPD, correlated positively with neutrophil-associated inflammatory/NET markers, and was inversely associated with eosinophil strata and lung function. CONCLUSION: Our study nominates PROK2⁺ neutrophils as a key pathogenic neutrophil subset in COPD and posits FOSL1 as a putative upstream driver. These findings suggest that PROK2 may serve as a candidate circulating biomarker associated with neutrophil-related inflammatory activity in COPD.

Source: Respiratory Research

DOI: 10.1186/s12931-026-03679-2