Feng Kang-Ni, Meng Ping, Zhang Min, Zou Xiao-Ling, Li Shuang, Huang Chu-Qin, Lai Ke-Fang, Li Hong-Tao, Zhang Tian-Tuo
Department of Pulmonary and Critical Care Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Institute of Respiratory Disease of Sun Yat-sen University, Guangzhou, China.
State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Allergy Asthma Immunol Res. 2022 Sep;14(5):505-527. doi: 10.4168/aair.2022.14.5.505.
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.
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.
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 . 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.
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.
嗜中性粒细胞性哮喘与哮喘加重、类固醇不敏感性及重度哮喘相关。白细胞介素（IL）-24在哮喘中过度表达，并参与多种变应性炎症性疾病的发病机制。然而，IL-24在嗜中性粒细胞性哮喘中的作用及具体机制尚不清楚。我们旨在阐明IL-24和IL-37在嗜中性粒细胞性哮喘中的作用、与IL-17A的关系以及调节嗜中性粒细胞性哮喘进展的机制。
从健康志愿者中分离纯化人嗜中性粒细胞，采用细胞共培养系统评估IL-24在上皮细胞源性IL-17A依赖性嗜中性粒细胞迁移中的功能。将IL-37或靶向IL-24的小干扰RNA（siRNA）经鼻给药，以验证其在屋尘螨（HDM）/脂多糖（LPS）诱导的嗜中性粒细胞性哮喘小鼠模型中的作用。
IL-24通过STAT3和ERK1/2信号通路增强支气管上皮细胞中IL-17A的产生；外源性IL-37可逆转此效应。抗IL-17A单克隆抗体可降低IL-24处理的上皮细胞诱导的嗜中性粒细胞趋化性。在HDM/LPS诱导的嗜中性粒细胞性哮喘中，观察到气道上皮中IL-24和IL-17A表达增加。给予IL-37或沉默IL-24可减轻嗜中性粒细胞性哮喘，降低IL-17A水平，减少嗜中性粒细胞气道浸润、气道高反应性和杯状细胞化生。在嗜中性粒细胞性哮喘模型的肺中，沉默IL-24可抑制辅助性T细胞17（Th17）免疫反应，但不抑制Th1或Th2免疫反应。
IL-24通过增加上皮细胞源性IL-17A的产生加重嗜中性粒细胞性气道炎症，IL-37可抑制此过程。靶向IL-24/IL-17A信号轴是一种潜在策略，IL-37是减轻哮喘中嗜中性粒细胞性气道炎症的潜在候选药物。
