| Autor: |
Zaid W. El-Husseini, Dmitry Khalenkow, Andy Lan, Thys van der Molen, Chris Brightling, Alberto Papi, Klaus F. Rabe, Salman Siddiqui, Dave Singh, Monica Kraft, Bianca Beghe, Maarten van den Berge, Djoke van Gosliga, Martijn C. Nawijn, Stefan Rose-John, Gerard H. Koppelman, Reinoud Gosens |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Respiratory Research, Vol 24, Iss 1, Pp 1-12 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
1465-993X |
| DOI: |
10.1186/s12931-023-02617-w |
| Popis: |
Abstract Background Asthma is stratified into type 2-high and type 2-low inflammatory phenotypes. Limited success has been achieved in developing drugs that target type 2-low inflammation. Previous studies have linked IL-6 signaling to severe asthma. IL-6 cooperates with soluble-IL-6Rα to activate cell signaling in airway epithelium. Objective We sought to study the role of sIL-6Rα amplified IL-6 signaling in airway epithelium and to develop an IL-6+ sIL-6Rα gene signature that may be used to select asthma patients who potentially respond to anti-IL-6 therapy. Methods Human airway epithelial cells were stimulated with combinations of IL-6, sIL-6Rα, and inhibitors, sgp130 (Olamkicept), and anti-IL-6R (Tocilizumab), to assess effects on pathway activation, epithelial barrier integrity, and gene expression. A gene signature was generated to identify IL-6 high patients using bronchial biopsies and nasal brushes. Results Soluble-IL-6Rα amplified the activation of the IL-6 pathway, shown by the increase of STAT3 phosphorylation and stronger gene induction in airway epithelial cells compared to IL-6 alone. Olamkicept and Tocilizumab inhibited the effect of IL-6 + sIL-6Rα on gene expression. We developed an IL-6 + sIL-6Rα gene signature and observed enrichment of this signature in bronchial biopsies but not nasal brushes from asthma patients compared to healthy controls. An IL-6 + sIL-6Rα gene signature score was associated with lower levels of sputum eosinophils in asthma. Conclusion sIL-6Rα amplifies IL-6 signaling in bronchial epithelial cells. Higher local airway IL-6 + sIL-6Rα signaling is observed in asthma patients with low sputum eosinophils. |
| Databáze: |
Directory of Open Access Journals |
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