Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Chem Biol Interact. 2019 May 1;304:52-60. doi: 10.1016/j.cbi.2019.03.001. Epub 2019 Mar 7.
Asthma, a chronic inflammatory disease affecting the airways is primarily caused due to immune system dysfunction. Different inhaled allergens such as house dust mites (HDM), fungi, cockroach allergens are the main contributors to allergic asthma. Protease activated receptor-2 (PAR-2) signaling plays an important role in allergic asthma through modulation of immune mediators in airway epithelial cells (AECs). Interleukin-17A (IL-17A) signals via subunits of IL-17 receptor (IL-17R), i.e. interleukin-17 receptor A (IL-17RA) and interleukin-17 receptor C (IL-17RC), and plays a necessary role in neutrophilic infiltration in response to infectious/allergenic stimuli, however it is not known if PAR-2 activation affects IL-17A/IL-17R signaling during acute exposure to house dust mite (HDM) allergens. Therefore, our study exposed mice to HDM allergens for five days and evaluated its effect on IL-17A/IL-17R signaling, chemokine/cytokines and neutrophilic inflammation in mice. Our study shows that HDM allergens upregulate IL-17A levels in the lung and IL-17RA/IL-17RC expression in AECs. PAR-2 activation by trypsin also upregulates neutrophilic influx and IL-17A/IL-17R signaling in the lung. Upregulated IL-17A/IL-17R signaling was associated with increased BAL neutrophils, pulmonary MPO activity and proinflammatory chemokines and cytokines (IL-23, IL-6, and MCP-1 in AECs/lung) in HDM exposed mice. Further, HDM-induced IL-17A, IL-17R and chemokines/cytokines were attenuated by PAR-2 antagonist, ENMD-1068. Furthermore, HDM-primed mice treated with IL-17A had greater neutrophilic inflammation and higher levels of inflammatory cytokines/chemokines than PBS-exposed mice treated with IL-17A. This proposes that acute exposure to HDM allergens activate AECs at a very early stage where PAR-2/IL-17R signaling serves a crucial role in neutrophilic inflammation.
哮喘是一种影响气道的慢性炎症性疾病，主要是由于免疫系统功能障碍引起的。不同的吸入性过敏原，如屋尘螨（HDM）、真菌、蟑螂过敏原，是过敏性哮喘的主要诱因。蛋白酶激活受体-2（PAR-2）信号通过调节气道上皮细胞（AECs）中的免疫介质在过敏性哮喘中发挥重要作用。白细胞介素-17A（IL-17A）通过白细胞介素-17 受体（IL-17R）的亚单位信号传导，即白细胞介素-17 受体 A（IL-17RA）和白细胞介素-17 受体 C（IL-17RC），在对感染/过敏刺激的中性粒细胞浸润中发挥必要作用，然而，PAR-2 激活是否影响急性暴露于屋尘螨（HDM）过敏原时的 IL-17A/IL-17R 信号传导尚不清楚。因此，我们的研究将小鼠暴露于 HDM 过敏原 5 天，评估其对 IL-17A/IL-17R 信号、趋化因子/细胞因子和中性粒细胞炎症的影响。我们的研究表明，HDM 过敏原上调肺中 IL-17A 水平和 AEC 中 IL-17RA/IL-17RC 的表达。胰蛋白酶激活 PAR-2 也上调肺中的中性粒细胞浸润和 IL-17A/IL-17R 信号。上调的 IL-17A/IL-17R 信号与 BAL 中性粒细胞、肺髓过氧化物酶活性和促炎趋化因子和细胞因子（AEC/肺中的 IL-23、IL-6 和 MCP-1）的增加相关。此外，PAR-2 拮抗剂 ENMD-1068 可减弱 HDM 诱导的 IL-17A、IL-17R 和趋化因子/细胞因子。此外，用 IL-17A 处理 HDM 预致敏的小鼠比用 PBS 处理的 IL-17A 处理的 PBS 暴露小鼠具有更大的中性粒细胞炎症和更高水平的炎症细胞因子/趋化因子。这表明，急性暴露于 HDM 过敏原会在非常早期阶段激活 AEC，其中 PAR-2/IL-17R 信号在中性粒细胞炎症中发挥关键作用。
