Abstract
IL-17A plays a critical role in the pathogenesis of steroid-resistant neutrophilic airway inflammation, which is a hallmark of severe asthma and chronic obstructive pulmonary disease (COPD). Through RNA sequencing analysis of transcriptomes of human airway smooth muscle cells treated with IL-17A, dexamethasone (DEX, a synthetic glucocorticoid drug), alone or in combination, we identified a group of genes that are synergistically induced by IL-17A and DEX, including the neutrophil-promoting cytokine CSF3. In type-17 (Th17/IL-17Ahi) preclinical models of neutrophilic severe asthma (acute and chronic) and COPD, although DEX treatment was able to reduce the expression of neutrophil-mobilizing CXCL1 and CXCL2 in lung tissue, CSF3 expression was upregulated by DEX treatment. We found that DEX treatment alone failed to alleviate neutrophilic airway inflammation and pathology, and even exacerbated the disease phenotype when CSF3 was highly induced. Disruption of the IL-17A/DEX synergy by IL-17A inhibition with anti-IL-17A mAb or cyanidin-3-glucoside (C3G, a small-molecule IL-17A blocker) or depletion of CSF3 effectively rendered DEX sensitivity in type-17 preclinical models of neutrophilic airway diseases. Our study elucidates what we believe is a novel mechanism of steroid resistance in type-17 neutrophilic airway inflammation and offers an effective steroid-sparing therapeutic strategy (combined low-dose DEX and C3G) for treating neutrophilic airway diseases.
Highlights
IL-17A, a major proinflammatory cytokine produced by Th17 cells, has been implicated as an important cytokine contributing to the pathogenesis of steroid-resistant neutrophilic airway diseases including severe asthma and chronic obstructive pulmonary disease (COPD) [1,2,3,4,5]
By employing Th17/IL-17Ahi preclinical mouse models of neutrophilic severe asthma and COPD, we showed that Csf3 expression was substantially induced in the lung tissue by DEX treatment, the expression of neutrophil-mobilizing Cxcl1 and Cxcl2 was decreased
DEX was able to further promote IL-17A/TNF–induced CSF3 expression in a synergistic manner, whereas DEX effectively suppressed the expression of CSF2, CXCL1, and CXCL2 (Figure 1B and Supplemental Figure 1A)
Summary
IL-17A, a major proinflammatory cytokine produced by Th17 cells, has been implicated as an important cytokine contributing to the pathogenesis of steroid-resistant neutrophilic airway diseases including severe asthma and chronic obstructive pulmonary disease (COPD) [1,2,3,4,5]. Glucocorticoids (GCs) are commonly used antiinflammatory therapeutic reagents to treat asthma and COPD. GC-based drugs can effectively manage Th2 inflammation via inducing apoptosis of Th2 cells and eosinophils and inhibiting type-2 cytokines, they have little efficacy in inhibiting Th17/IL-17Ahi neutrophilic severe asthma and COPD that are steroid resistant or refractory [7, 13,14,15]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
