Human cystatin SN is an endogenous protease inhibitor that prevents allergic rhinitis
Human cystatin SN is an endogenous protease inhibitor that prevents allergic rhinitis
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DOI：
10.1016/j.jaci.2018.06.035
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发表时间：
2019-03-01
影响因子：
14.2
通讯作者：
Yoshimoto, Tomohiro
中科院分区：
文献类型：
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作者：
Fukuoka, Ayumi;Matsushita, Kazufumi;Yoshimoto, Tomohiro
背景：蛋白酶变应原破坏上皮屏障发挥其变应原性。胱抑素SN（由CST 1编码）是一种内源性半胱氨酸蛋白酶抑制剂，在变应性鼻炎（AR）患者鼻上皮中上调。目的：我们试图利用花粉诱导的AR小鼠模型研究人半胱氨酸蛋白酶抑制剂SN对AR症状的保护作用。我们进行了体外蛋白酶活性测定，以评估重组人胱抑素SN的作用（rhCystatin SN）对日本雪松（JC）或豚草蛋白酶的作用。人鼻上皮细胞系RPMI 2650，用于检查紧密连接（TJ）的破坏在体外。用JC或豚草花粉致敏小鼠，并在有或没有rhCystatinSN的情况下用鼻腔激发，以检查rhCystatinSN对体内AR症状和上皮屏障的影响。由于小鼠缺乏CST 1，我们产生的转基因（Tg）小鼠表达的人CST 1的基因组控制区（hCST 1-Tg小鼠）的控制下，检查的作用，半胱氨酸蛋白酶抑制剂SN在生理表达conditions.Results：rhCystatin SN抑制JC，但不豚草蛋白酶活性，并防止JC诱导，但不豚草诱导的TJ破坏在体外。外源性给予rhCystatin SN可改善JC诱导的喷嚏和鼻腔TJ破坏，但对豚草诱导的喷嚏和鼻腔TJ破坏无改善作用。此外，hCST 1-Tg小鼠表现出减少JC诱导的，但不是豚草诱导的打喷嚏症状和鼻TJ中断与wild-type mice.Conclusion相比：人胱抑素SN抑制AR症状，通过抑制过敏原蛋白酶的活性和保护鼻TJ屏障在过敏原特异性的方式。我们认为，上调鼻内源性蛋白酶抑制剂，包括半胱氨酸蛋白酶抑制剂SN，是蛋白酶过敏原诱导的AR的一种新的治疗策略。
Background: Protease allergens disrupt epithelial barriers to exert their allergenicity. Cystatin SN (encoded by CST1) is an endogenous cysteine protease inhibitor upregulated in nasal epithelia in patients with allergic rhinitis (AR).Objective: We sought to investigate the protective effect of human cystatin SN on AR symptoms using pollen-induced AR mouse models.Methods: We performed an in vitro protease activity assay to evaluate the effect of recombinant human cystatin SN (rhCystatin SN) on Japanese cedar (JC) or ragweed proteases. A human nasal epithelial cell line, RPMI 2650, was used to examine tight junction (TJ) disruption in vitro. Mice were sensitized and nasally challenged with JC or ragweed pollens with or without rhCystatin SN to examine the effect of rhCystatin SN on AR symptoms and the epithelial barrier in vivo. Because mice lack CST1, we generated transgenic (Tg) mice expressing human CST1 under control of its genomic control region (hCST1-Tg mice) to examine the role of cystatin SN in physiologically expressed conditions.Results: rhCystatin SN inhibited JC but not ragweed protease activities and prevented JC-induced but not ragweed-induced TJ disruption in vitro. Exogenous administration of rhCystatin SN ameliorated JC-induced but not ragweed-induced sneezing and nasal TJ disruption in vivo. Furthermore, hCST1-Tg mice showed decreased JC-induced but not ragweed-induced sneezing symptoms and nasal TJ disruption compared with wild-type mice.Conclusion: Human cystatin SN suppresses AR symptoms through inhibiting allergen protease activities and protecting the nasal TJ barrier in an allergen-specific manner. We propose that upregulation of nasal endogenous protease inhibitors, including cystatin SN, is a novel therapeutic strategy for protease allergen-induced AR.