Ayumi Fukuoka1, Kazufumi Matsushita2, Taiyo Morikawa3, Takumi Adachi4, Koubun Yasuda4, Hiroshi Kiyonari5, Shigeharu Fujieda6, Tomohiro Yoshimoto2. 1. Department of Immunology, Hyogo College of Medicine, Nishinomiya, Japan. Electronic address: afukuoka@hyo-med.ac.jp. 2. Department of Immunology, Hyogo College of Medicine, Nishinomiya, Japan; Laboratory of Allergic Diseases, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Japan. 3. Laboratory of Allergic Diseases, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Japan; Department of Otorhinolaryngology-Head and Neck Surgery, Faculty of Medical Science, University of Fukui, Fukui, Japan. 4. Department of Immunology, Hyogo College of Medicine, Nishinomiya, Japan. 5. Animal Resource Development Unit and Genetic Engineering Team, RIKEN Center for Life Science Technologies, Kobe, Japan. 6. Department of Otorhinolaryngology-Head and Neck Surgery, Faculty of Medical Science, University of Fukui, Fukui, Japan.
Abstract
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.
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 humancystatin 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 humancystatin 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 humanCST1 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:Humancystatin 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.
Authors: Angela L Nocera; Sarina K Mueller; Alan D Workman; Dawei Wu; Kristen McDonnell; Peter M Sadow; Mansoor M Amiji; Benjamin S Bleier Journal: J Allergy Clin Immunol Date: 2022-05-31 Impact factor: 14.290
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