Steroid-induced fibroblast growth factors drive an epithelial-mesenchymal inflammatory axis in severe asthma

Author:

Guidi Riccardo1ORCID,Xu Daqi1,Choy David F.2ORCID,Ramalingam Thirumalai R.2,Lee Wyne P.3ORCID,Modrusan Zora4,Liang Yuxin4,Marsters Scot5ORCID,Ashkenazi Avi5ORCID,Huynh Alison6,Mills Jessica6ORCID,Flanagan Sean6ORCID,Hambro Shannon6ORCID,Nunez Victor6ORCID,Leong Laurie7ORCID,Cook Ashley7,Tran Tiffany Hao7ORCID,Austin Cary D.7ORCID,Cao Yi8,Clarke Christine8ORCID,Panettieri Reynold A.9ORCID,Koziol-White Cynthia9ORCID,Jester William F.9ORCID,Wang Fen10ORCID,Wilson Mark S.1ORCID

Affiliation:

1. Immunology Discovery, Genentech, South San Francisco, CA 94080, USA.

2. Biomarker Discovery OMNI, Genentech, South San Francisco, CA 94080, USA.

3. Translational Immunology, Genentech, South San Francisco, CA 94080, USA.

4. Next Generation Sequencing (NGS), Genentech, South San Francisco, CA 94080, USA.

5. Cancer Immunology, Genentech, South San Francisco, CA 94080, USA.

6. Necropsy, Genentech, South San Francisco, CA 94080, USA.

7. Pathology, Genentech, South San Francisco, CA 94080, USA.

8. OMNI Bioinformatics, Genentech, South San Francisco, CA 94080, USA.

9. Institute for Translational Medicine and Science, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA.

10. Center for Cancer Biology and Nutrition, Texas A&M University, Houston, TX 77030, USA.

Abstract

Asthma and inflammatory airway diseases restrict airflow in the lung, compromising gas exchange and lung function. Inhaled corticosteroids (ICSs) can reduce inflammation, control symptoms, and improve lung function; however, a growing number of patients with severe asthma do not benefit from ICS. Using bronchial airway epithelial brushings from patients with severe asthma or primary human cells, we delineated a corticosteroid-driven fibroblast growth factor (FGF)–dependent inflammatory axis, with FGF-responsive fibroblasts promoting downstream granulocyte colony-stimulating factor (G-CSF) production, hyaluronan secretion, and neutrophilic inflammation. Allergen challenge studies in mice demonstrate that the ICS, fluticasone propionate, inhibited type 2–driven eosinophilia but induced a concomitant increase in FGFs, G-CSF, hyaluronan, and neutrophil infiltration. We developed a model of steroid-induced neutrophilic inflammation mediated, in part, by induction of an FGF-dependent epithelial-mesenchymal axis, which may explain why some individuals do not benefit from ICS. In further proof-of-concept experiments, we found that combination therapy with pan-FGF receptor inhibitors and corticosteroids prevented both eosinophilic and steroid-induced neutrophilic inflammation. Together, these results establish FGFs as therapeutic targets for severe asthma patients who do not benefit from ICS.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

General Medicine

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Obese asthma phenotypes display distinct plasma biomarker profiles;Clinical and Translational Allergy;2023-03

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