Targeting the neutrophil-DPP-1-protease axis in airway disease: current evidence and future indications.

Neutrophils contribute to chronic airway diseases with variable pathogenic relevance across conditions. In bronchiectasis, persistent airway neutrophilia and sustained activity of neutrophil serine proteases (NSPs) - neutrophil elastase (NE), proteinase 3 (PR3), and cathepsin G (CatG) - directly drive structural damage and exacerbations. In Chronic Obstructive Pulmonary Disease (COPD), neutrophils participate in parenchymal destruction and systemic inflammation within a broader network of oxidative and immune dysregulation. In T2-low asthma, neutrophilic inflammation is heterogeneous and context-dependent, suggesting a less uniform contribution of NSP-mediated injury. Therapeutic strategies targeting neutrophils downstream have yielded limited clinical success: selective NE inhibitors and C-X-C motif chemokine receptor 2 (CXCR2) antagonists reduced protease activity or neutrophil recruitment but failed to produce consistent improvements in lung function or exacerbation rates. These evidences reflect redundancy among NSPs, compensatory inflammatory pathways, and the presence of pre-activated circulating neutrophils whose proteolytic potential is already established before tissue recruitment. This has shifted attention upstream to the neutrophil-DPP-1-protease axis. Dipeptidyl peptidase-1 (DPP-1) activates NSPs during neutrophil maturation in the bone marrow; its inhibition reduces the protease load of circulating neutrophils without broadly suppressing innate immunity. In bronchiectasis, DPP-1 inhibitors have demonstrated clinically meaningful reductions in exacerbations and airway NSP activity, providing proof of concept for disease modification. In COPD, this strategy is biologically compelling, particularly in neutrophil-predominant phenotypes, but requires dedicated clinical validation. In asthma, any therapeutic role is likely restricted to highly selected T2-low, neutrophil-driven subsets. Future progress will depend on biomarker-guided stratification to define where modulation of the neutrophil-NSP axis can meaningfully alter disease trajectory.