School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
Department of Emergency, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
Int J Mol Sci. 2022 Aug 20;23(16):9405. doi: 10.3390/ijms23169405.
House dust mites (HDMs) are a common source of respiratory allergens responsible for allergic asthma and innate immune responses in human diseases. Since HDMs are critical factors in the triggering of allergen-induced airway mucosa from allergic asthma, we aimed to investigate the mechanisms of Toll-like receptors (TLR) in the signaling of the HDM extract that is involved in mucus hypersecretion and airway inflammation through the engagement of innate immunity. Previously, we reported that the somatic nuclear autoantigenic sperm protein (sNASP)/tumor necrosis factor receptor-associated factor 6 (TRAF6) axis controls the initiation of TLRs to maintain the homeostasis of the innate immune response. The present study showed that the HDM extract stimulated the biogenesis of Mucin 5AC (MUC5AC) in bronchial epithelial cells via the TLR2/4 signaling pathway involving MyD88 and TRAF6. Specifically, sNASP binds to TRAF6 in unstimulated bronchial epithelial cells to prevent the activation of TRAF6-depenedent kinases. Upon on HDMs' stimulation, sNASP is phosphorylated, leading to the activation of TRAF6 downstream of the p38 MAPK and NF-κB signaling pathways. Further, NASP-knockdown enhanced TRAF6 signaling and MUC5AC biogenesis. In the HDM-induced mouse asthma model, we found that the HDM extract promoted airway hyperresponsiveness (AHR), MUC5AC, and allergen-specific IgE production as well as IL-5 and IL-13 for recruiting inflammatory cells. Treatment with the PEP-NASP peptide, a selective TRAF6-blocking peptide, ameliorated HDM-induced asthma in mice. In conclusion, this study indicated that the sNASP/TRAF6 axis plays a regulatory role in asthma by modulating mucus overproduction, and the PEP-NASP peptide might be a potential target for asthma treatment.
屋尘螨（HDM）是引起呼吸道过敏的常见过敏原，也是人类疾病中过敏哮喘和固有免疫反应的原因。由于 HDM 是诱发过敏哮喘气道黏膜的关键因素，我们旨在研究 Toll 样受体（TLR）在 HDM 提取物信号转导中的机制，该信号转导通过固有免疫参与黏液高分泌和气道炎症。此前，我们报道体细胞核自身抗原精子蛋白（sNASP）/肿瘤坏死因子受体相关因子 6（TRAF6）轴控制 TLR 的启动，以维持固有免疫反应的内稳状态。本研究表明，HDM 提取物通过 TLR2/4 信号通路（涉及 MyD88 和 TRAF6）刺激支气管上皮细胞的粘蛋白 5AC（MUC5AC）的生物发生。具体而言，sNASP 在未受刺激的支气管上皮细胞中与 TRAF6 结合，以阻止 TRAF6 依赖性激酶的激活。在 HDM 刺激下，sNASP 被磷酸化，导致 p38 MAPK 和 NF-κB 信号通路下游的 TRAF6 激活。此外，sNASP 敲低增强了 TRAF6 信号和 MUC5AC 的生物发生。在 HDM 诱导的小鼠哮喘模型中，我们发现 HDM 提取物促进气道高反应性（AHR）、MUC5AC 和过敏原特异性 IgE 产生以及招募炎症细胞的 IL-5 和 IL-13。用 PEP-NASP 肽（一种选择性 TRAF6 阻断肽）治疗可改善小鼠的 HDM 诱导性哮喘。总之，本研究表明 sNASP/TRAF6 轴通过调节黏液过度产生在哮喘中发挥调节作用，PEP-NASP 肽可能是哮喘治疗的潜在靶点。
