Department of Otolaryngology-Head and Neck Surgery, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, U.S.A.
the Center for Immunology and Autoimmune Diseases, Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, U.S.A.
Laryngoscope. 2019 Oct;129(10):2230-2235. doi: 10.1002/lary.28000. Epub 2019 Apr 11.
In the pathophysiology of chronic rhinosinusitis with nasal polyps (CRSwNP), Aspergillus fumigatus (A. fumigatus) can upregulate IL-33 from human sinonasal epithelial cells (SNECs), which then activates innate lymphoid cells causing release of IL-13, an important driver of allergic inflammation. However, the mechanism by which A. fumigatus mediates the induction of IL-33 expression remains to be elucidated. The objectives of this study were to determine the specific fungal component(s) and the receptor responsible for mediating the A. fumigatus induced increase in IL-33 expression in SNECs from patients with CRSwNP.
SNECs from CRSwNP patients were cultured and stimulated with various fungal components in the absence or presence of 4-(2-Aminoethyl)benzenesulfonyl fluoride hydrochloride, an irreversible serine protease inhibitor, or GB83, a reversible protease activated receptor 2 (PAR2) inhibitor. IL-33 expression was evaluated using quantitative real-time polymerase chain reaction (qRT-PCR). PAR2 expression was examined in inflamed mucosa from nonatopic control and CRSwNP patients.
Elevation of IL-33 expression in primary SNECs was found in response to fungal protease but not fungal cell wall components. PAR2 expression was elevated in inflamed mucosa from CRSwNP patients in comparison to controls. The A. fumigatus fungal protease-mediated elevation in IL-33 expression by human SNECs was serine protease- and PAR2-dependent.
These data suggest that serine protease activity of A. fumigatus is capable of inducing IL-33 expression in CRSwNP SNECs via PAR2, a potential therapeutic target in the treatment of CRSwNP.
NA Laryngoscope, 129:2230-2235, 2019.
在伴有鼻息肉的慢性鼻-鼻窦炎（CRSwNP）的病理生理学中，烟曲霉（A. fumigatus）可使人类鼻黏膜上皮细胞（SNECs）中的白细胞介素 33（IL-33）上调，继而激活天然淋巴细胞，导致白细胞介素 13（IL-13）的释放，这是过敏炎症的一个重要驱动因素。然而，A. fumigatus 介导诱导 IL-33 表达的机制仍有待阐明。本研究旨在确定特定的真菌成分及其受体，以介导烟曲霉诱导的 CRSwNP 患者 SNECs 中 IL-33 表达的增加。
培养 CRSwNP 患者的 SNECs，并用各种真菌成分在不存在或存在 4-（2-氨乙基）苯磺酰氟盐酸盐（不可逆丝氨酸蛋白酶抑制剂）或 GB83（可逆蛋白酶激活受体 2（PAR2）抑制剂）的情况下刺激 SNECs。采用实时定量聚合酶链反应（qRT-PCR）评估 IL-33 表达。检测非变应性对照和 CRSwNP 患者炎症黏膜中 PAR2 的表达。
在原代 SNECs 中发现真菌蛋白酶而非真菌细胞壁成分的升高可引起 IL-33 表达的升高。与对照组相比，CRSwNP 患者的炎症黏膜中 PAR2 的表达升高。与对照组相比，A. fumigatus 真菌蛋白酶介导的人 SNECs 中 IL-33 表达的升高依赖于丝氨酸蛋白酶和 PAR2。
这些数据表明，A. fumigatus 的丝氨酸蛋白酶活性能够通过 PAR2 诱导 CRSwNP SNECs 中 IL-33 的表达，PAR2 可能成为治疗 CRSwNP 的潜在治疗靶点。
NA Laryngoscope, 129:2230-2235, 2019.
