Role of NETosis in the Pathogenesis of Respiratory Diseases: Molecular Mechanisms and Emerging Insights

Abstract

Neutrophil extracellular trap (NET) formation or NETosis is a specialized innate immune process in which neutrophils release chromatin fibers decorated with histones and antimicrobial proteins. Although pivotal for pathogen clearance, aberrant NETosis has emerged as a critical modulator of acute and chronic respiratory pathologies, including acute respiratory distress syndrome, asthma, and chronic obstructive pulmonary disease. Dysregulated NET release exacerbates airway inflammation by inducing epithelial injury, mucus hypersecretion, and the recruitment of inflammatory leukocytes, thereby accelerating tissue remodeling and functional decline. Mechanistically, NETosis is governed by peptidyl arginine deiminase 4 (PADI4)-mediated histone citrullination, NADPH oxidase-dependent reactive oxygen species production, mitochondrial metabolic reprogramming, and activation of toll-like receptors and inflammasomes. These molecular events perpetuate inflammation and prevent its resolution. Emerging evidence indicates that natural bioactive compounds, such as flavonoids, terpenoids, and polyphenols, attenuate NETosis by modulating oxidative stress, inhibiting PADI4 activation, or suppressing downstream pro-inflammatory cascades. Collectively, these findings highlight the therapeutic potential of targeting NETosis to mitigate neutrophil-driven airway pathology. This review aims to comprehensively synthesize recent mechanistic insights into NETosis and to delineate how modulation of NET formation contributes to the prevention and treatment of inflammatory respiratory diseases.