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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

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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 3

Small-molecule IL-17A blocker C3G alleviates neutrophilia and improves DEX sensitivity in HDM-CFA type-17 acute asthma model.

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Small-molecule IL-17A blocker C3G alleviates neutrophilia and improves D...
(A) Chemical structure of C3G. (B) Human and mouse ASMCs (hASMCs and mASMCs) were treated for 24 hours with IL-17A in the presence of DMSO (vehicle control) or the indicated concentrations of C3G. The concentrations of CXCL1 (GROα in humans and KC in mice) in the culture medium were measured by ELISA. Results are presented as a percentage of the amount of CXCL1 in the culture medium of DMSO-treated cells, which was set at 100%. Data are representative of 3 independent experiments. Error bars represent the SEM of technical replicates. (C and D) Eight-week-old WT C57BL/6 female mice (n = 5 per group) were subjected to the HDM-CFA acute asthma model. PBS (Control), DEX, C3G, or a combination of DEX and C3G were administered to the mice (as described in Methods). Twenty-four hours after challenging, total and neutrophil counts in the BAL were quantified (C). Representative BAL cells were prepared by cytospin and lung tissues were stained with H&E (D). All scale bars (red): 100 μm. (E) mRNA expression of lung tissues was quantified by real-time PCR. (F and G) OVA323–339-specific Th17 cells were adoptively transferred into 8-week-old female C57BL/6 mice (n = 5 mice per treatment group), which were treated as described in Methods. Twenty-four hours after the last challenge, total cell and neutrophil counts in the BAL were quantified. 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.

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