Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Navigation/Suche
- Forscher*innen
- Institutionen
- Projekte
- Publikationen
- Partner
- Geldgeber
- Ausstattung
- Knowhow
- Forschungsfelder
"Köpfe" der aktuellen Meldungen:
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Nayak, BB; Bärnthaler, T; Rajesh, R; Teppan, J; Gogg, T; Douschan, P; Kneidinger, N; van, der, Does, AM; Hiemstra, P; Heinemann, A; Böhm, E.
Brepocitinib, a selective TYK2/JAK1 inhibitor, mitigates neutrophilic inflammation and glucocorticoid receptor-β expression in COPD.
Am J Physiol Lung Cell Mol Physiol. 2026;
Doi: 10.1152/ajplung.00237.2025
PubMed
FullText
FullText_MUG
- Führende Autor*innen der Med Uni Graz
- Böhm Eva
- Nayak Barsha Baisakhi
- Co-Autor*innen der Med Uni Graz
- Bärnthaler Thomas
- Douschan Philipp
- Gogg Theresa
- Heinemann Akos
- Kneidinger Nikolaus
- Rajesh Rishi
- Teppan Julia
- Altmetrics:
- Dimensions Citations:
- Plum Analytics:
- Scite (citation analytics):
- Abstract:
- 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 COPD patients 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 COPD patients 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.