Brepocitinib, a selective TYK2/JAK1 inhibitor, mitigates neutrophilic inflammation and glucocorticoid receptor-β...

Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder characterized by neutrophil-dominant, corticosteroid-refractory airway inflammation involving the IL-23/IL-17A axis. IL-23 primarily activates the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway through TYK2 and JAK2, whereas IL-17A and other pro-inflammatory cytokines can activate JAK1. However, the contribution of these JAK-dependent pathways to neutrophil-driven inflammation in COPD remains incompletely understood. In this study, we investigated how the IL-23/IL-17A axis modulates neutrophil function and evaluated the therapeutic potential of the dual TYK2/JAK1 inhibitor brepocitinib in COPD. Gene expression and flow cytometric analyses revealed increased TYK2 and JAK1 expression and phosphorylation in sputum cells and neutrophils from patients with COPD and smokers. IL-23 and IL-17A enhanced neutrophil activation and stimulated IL-8 release from bronchial epithelial cells, effects that were abrogated by brepocitinib. Neutrophils from patients with COPD and smokers also exhibited elevated GRβ expression, a mechanism associated with corticosteroid resistance, which was recapitulated by IL-23/IL-17A stimulation and reversed by brepocitinib. In vivo, brepocitinib suppressed neutrophil recruitment induced by IL-23 or LPS in acute inflammation models. Overall, these findings demonstrate that TYK2/JAK1 inhibition mitigates IL-23/IL-17A-induced neutrophil-driven inflammation and GRβ upregulation in COPD. This highlights the JAK/STAT pathway as a promising therapeutic target to overcome severe airway inflammation and restore GRα/GRβ balance in neutrophils.NEW & NOTEWORTHY This study reveals that the IL-23/IL-17A axis drives neutrophil activation and GRβ upregulation in COPD through TYK2/JAK1-mediated signaling. Inhibition of TYK2/JAK1 with brepocitinib reduced neutrophilic inflammation and restored the GRα/GRβ balance in neutrophils, identifying TYK2/JAK1 as promising therapeutic targets for severe COPD.