Early IL-17A Prevention Rather Than Late IL-17A Neutralization Attenuates Toluene Diisocyanate-Induced Mixed Granulocytic Asthma

Shuyu Chen; Li Yu; Yao Deng; Yuanyuan Liu; Lingwei Wang; Difei Li; Kai Yang; Shengming Liu; Ailin Tao; Rongchang Chen

doi:10.4168/aair.2022.14.5.528

Early IL-17A Prevention Rather Than Late IL-17A Neutralization Attenuates Toluene Diisocyanate-Induced Mixed Granulocytic Asthma

Allergy Asthma Immunol Res. 2022 Sep;14(5):528-548. doi: 10.4168/aair.2022.14.5.528.

Authors

Shuyu Chen^#^{1

2}, Li Yu^#¹, Yao Deng^#¹, Yuanyuan Liu^#^{1

2}, Lingwei Wang¹, Difei Li¹, Kai Yang^{1

2}, Shengming Liu², Ailin Tao³, Rongchang Chen⁴

Affiliations

¹ Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, Shenzhen Key Laboratory of Respiratory Diseases, The Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People's Hospital), Shenzhen, China.
² Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital of Jinan University, Guangzhou, China.
³ The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China. taoailin@gzhmu.edu.cn.
⁴ Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, Shenzhen Key Laboratory of Respiratory Diseases, The Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People's Hospital), Shenzhen, China. chenrc@vip.163.com.

^# Contributed equally.

Abstract

Purpose: Interleukin (IL)-17A plays a critical role in the pathogenesis of allergic airway inflammation. Yet, the exact roles of IL-17A in asthma are still controversial. Thus, the aim of this study was to dissect the roles of IL-17A in toluene diisocyanate (TDI)-induced mixed granulocytic asthma and to assess the effects of neutralizing antibody in different effector phases on TDI-induced asthma.

Methods: IL-17A functions in allergic airway inflammation were evaluated using mice deficient in IL-17A (Il17a^-/-) or IL-17A monoclonal antibody (IL-17A mab, intraperitoneally, 50 μg per mouse, 100 μg per mouse). Moreover, the effects of exogenous recombinant IL (rIL)-17A in vivo (murine rIL-17A, intranasally, 1 μg per mouse) and in vitro (human rIL-17A, 100 ng/mL) were investigated.

Results: TDI-induced mixed granulocytic airway inflammation was IL-17A-dependent because airway hyperreactivity, neutrophil and eosinophil infiltration, airway smooth muscle thickness, epithelium injury, dysfunctional T helper (Th) 2 and Th17 responses, granulocytic chemokine production and mucus overproduction were more markedly reduced in the Il17a^-/- mice or by IL-17A neutralization during the sensitization phase of wild-type (WT) mice. By contrast, IL-17A neutralization during the antigen-challenge phase aggravated TDI-induced eosinophils recruitment, with markedly elevated Th2 response. In line with this, instillation of rIL-17 during antigen sensitization exacerbated airway inflammation by promoting neutrophils aggregation, while rIL-17A during the antigen-challenge phase protected the mice from TDI-induced airway eosinophilia. Moreover, rIL-17A exerted distinct effects on eosinophil- or neutrophil-related signatures in vitro.

Conclusions: Our data demonstrated that IL-17A was required for the initiation of TDI-induced asthma, but functioned as a negative regulator of established allergic inflammation, suggesting that early abrogation of IL-17A signaling, but not late IL-17A neutralization, may prevent the progression of TDI-induced asthma and could be used as a therapeutic strategy for severe asthmatics in clinical settings.

Keywords: Asthma; IL-17A; dual effects; early intervention; toluene diisocyanate.