Human cystatin SN is an endogenous protease inhibitor that prevents allergic rhinitis

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:143

Article

Fukuoka, Ayumi¹  Matsushita, Kazufumi^1,2  Morikawa, Taiyo^2,3  Adachi, Takumi¹  Yasuda, Koubun¹  Kiyonari, Hiroshi^4,5  Fujieda, Shigeharu³  Yoshimoto, Tomohiro^1,2 

[1] Hyogo Coll Med, Dept Immunol, Nishinomiya, Hyogo 6638501, Japan

[2] Hyogo Coll Med, Inst Adv Med Sci, Lab Allerg Dis, Nishinomiya, Hyogo, Japan

[3] Univ Fukui, Fac Med Sci, Dept Otorhinolaryngol Head & Neck Surg, Fukui, Japan

[4] RIKEN Ctr Life Sci Technol, Anim Resource Dev Unit, Kobe, Hyogo, Japan

[5] RIKEN Ctr Life Sci Technol, Genet Engn Team, Kobe, Hyogo, Japan

关键词: Allergic rhinitis;    cystatin SN;    nasal epithelial cells;    protease;    tight junctions;   

DOI  :  10.1016/j.jaci.2018.06.035

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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