Aspergillus fumigatus induction of IL-33 expression in chronic rhinosinusitis is PAR2-dependent
Aspergillus fumigatus induction of IL-33 expression in chronic rhinosinusitis is PAR2-dependent
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DOI：
10.1002/lary.28000
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发表时间：
2019-10-01
期刊：
影响因子：
2.6
通讯作者：
Luong, Amber U.
中科院分区：
文献类型：
--
作者：
Dietz, Caroline J.;Sun, Hua;Luong, Amber U.
目的在慢性鼻窦炎鼻息肉(CRSwNP)的病理生理过程中，烟曲霉菌(Aspergillusfumigatus)可上调人鼻窦上皮细胞(SNECs)分泌IL-33，进而激活先天淋巴样细胞，释放IL-13，这是导致变应性炎症的重要因素。然而，烟曲霉菌诱导IL-33表达的机制尚不清楚。本研究的目的是确定特异性真菌成分(S)和介导烟曲霉菌诱导CRSwNP患者SNECs IL-33表达增加的受体。方法不可逆丝氨酸蛋白酶抑制剂4-(2-氨基乙基)苯磺酰氟盐酸盐或可逆蛋白酶激活受体2(PAR2)抑制剂GB83单独或联合作用于CRSwNP患者的SNECs。用实时定量聚合酶链式反应(qRT-PCR)检测IL-33的表达。检测非特应性对照组和CRSwNP患者炎症黏膜中PAR2的表达。结果原代培养的SNECs在真菌蛋白水解酶作用下，IL-33的表达增加，而对真菌细胞壁成分的作用不明显。CRSwNP患者炎性黏膜中PAR2的表达高于对照组。烟曲霉真菌蛋白水解酶对人SNECs IL-33表达的上调是丝氨酸蛋白酶和PAR2依赖的。结论烟曲霉丝氨酸蛋白酶活性可通过PAR2途径诱导CRSwNP SNECs表达IL-33，是治疗CRSwNP的潜在靶点。证据级别NA喉镜，129：2230-2235,2019年
Objective 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. Methods 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. Results 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. Conclusion 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. Level of Evidence NA Laryngoscope, 129:2230-2235, 2019