IL-24 Contributes to Neutrophilic Asthma in an IL-17A-Dependent Manner and Is Suppressed by IL-37

Purpose: Neutrophilic asthma is associated with asthma exacerbation, steroid insensitivity, and severe asthma. Interleukin (IL)-24 is overexpressed in asthma and is involved in the pathogenesis of several allergic inflammatory diseases. However, the role and specific mechanism of IL-24 in neutrophilic asthma are unclear. We aimed to elucidate the roles of IL-24 and IL-37 in neutrophilic asthma, the relationships with IL-17A and the mechanisms regulating neutrophilic asthma progression.Methods: Purified human neutrophils were isolated from healthy volunteers, and a cell coculture system was used to evaluate the function of IL-24 in epithelium-derived IL-17A -dependent neutrophil migration. IL-37 or a small interfering RNA (siRNA) targeting IL-24 was delivered intranasally to verify the effect in a murine model of house dust mite (HDM)/ lipopolysaccharide (LPS)-induced neutrophilic asthma.Results: IL-24 enhanced IL-17A production in bronchial epithelial cells via the STAT3 and ERK1/2 signaling pathways; this effect was reversed by exogenous IL-37. Anti-IL-17A monoclonal antibodies reduced neutrophil chemotaxis induced by IL-24-treated epithelial cells in vitro. Increased IL-24 and IL-17A expression in the airway epithelium was observed in HDM/LPS-induced neutrophilic asthma. IL-37 administration or IL-24 silencing attenuated neutrophilic asthma, reducing IL-17A levels and decreasing neutrophil airway infiltration, airway hyperresponsiveness, and goblet cell metaplasia. Silencing IL-24 inhibited T-helper 17 (Th17) immune responses, but not Th1 or Th2 immune responses, in the lungs of a neutrophilic asthma model.Conclusions: IL-24 aggravated neutrophilic airway inflammation by increasing epithelium -derived IL-17A production, which could be suppressed by IL-37. Targeting the IL-24/IL-17A signaling axis is a potential strategy, and IL-37 is a potential candidate agent for alleviating neutrophilic airway inflammation in asthma.