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

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.

IL‐17A facilitates type 2 inflammation in a modified eosinophilic chronic rhinosinusitis mouse model

“…injection with recombinant IL‐17A could increase IL‐17A expression in the lung of a chronic obstructive pulmonary disease murine model 35 . It has also been reported that administered recombinant IL‐17A via direct intranasal administration could obtain positive effects of overexpression of IL‐17A in the lung of a murine asthma model 36 . Therefore, these two strategies to administer recombinant IL‐17A demonstrated effectiveness.…”

“…35 It has also been reported that administered recombinant IL-17A via direct intranasal administration could obtain positive effects of overexpression of IL-17A in the lung of a murine asthma model. 36 Therefore, these two strategies to administer recombinant IL-17A demonstrated effectiveness. Here, we observed that IL-17A caused upregulation of type 2 cytokine levels such as IL-4, IL-5, and IL-13 in the NLF and CD4-, IL-4-, and ECP-positive cells in the nasal mucosa of ECRS mice.…”