Targeting IL-17A/glucocorticoid synergy to CSF3 expression in neutrophilic airway diseases
Suidong Ouyang, Caini Liu, Jianxin Xiao, Xing Chen, Andy C. Lui, Xiaoxia Li
Suidong Ouyang, Caini Liu, Jianxin Xiao, Xing Chen, Andy C. Lui, Xiaoxia Li
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Research Article Immunology Inflammation

Targeting IL-17A/glucocorticoid synergy to CSF3 expression in neutrophilic airway diseases

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.

Authors

Suidong Ouyang, Caini Liu, Jianxin Xiao, Xing Chen, Andy C. Lui, Xiaoxia Li

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Figure 2

Disruption of IL-17A/DEX synergistic effect on CSF3 expression renders DEX sensitivity in HDM-CFA type-17 acute asthma model.

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Disruption of IL-17A/DEX synergistic effect on CSF3 expression renders D...
(A) Eight-week-old WT C57BL/6 female mice (n = 5 per group) were subjected to the HDM-CFA acute severe asthma model. Isotype antibody (Control), DEX, anti-CSF3, and anti–IL-17A neutralizing antibodies or combined DEX and antibodies were administered to the mice (as described in Methods). Twenty-four hours after challenging, total cell and neutrophil counts in the BAL were quantified. (B) mRNA expression of lung tissues was quantified by real-time PCR. AU, fold induction relative to unchallenged control mice. Data represent mean ± SEM. One-way ANOVA was performed, followed by Tukey’s multiple-comparisons test. The multiplicity-adjusted P values were calculated for the indicated comparisons. The above data are representative of 3 independent experiments.