Airway inflammation after epicutaneous sensitization of mice requires protease activity of low-dose allergen inhalation Izumi Nishioka, MD, PhD, Toshiro.

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Airway inflammation after epicutaneous sensitization of mice requires protease activity of low-dose allergen inhalation Izumi Nishioka, MD, PhD, Toshiro Takai, PhD, Natsuko Maruyama, MSc, Seiji Kamijo, PhD, Punyada Suchiva, MD, MSc, Mayu Suzuki, MSc, Shinya Kunimine, MD, Hirono Ochi, MD, PhD, Sakiko Shimura, MD, PhD, Katsuko Sudo, PhD, Hideoki Ogawa, MD, PhD, Ko Okumura, MD, PhD, Shigaku Ikeda, MD, PhD Journal of Allergy and Clinical Immunology Volume 141, Issue 6, Pages 2271-2273.e7 (June 2018) DOI: 10.1016/j.jaci.2017.11.035 Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Allergic airway inflammation and maintenance of IgE levels induced by airway exposure to a low dose of papain in epicutaneously presensitized mice. Papain was intranasally administered to epicutaneously presensitized (A-C) or naive mice (D-F). A and D, Time lines. B and E, Airway eosinophilia. C and F, Serum total and papain-specific IgE levels (before [day 12] or after the intranasal challenge [day 22]). Data are indicated as the mean ± SD of 5 or 4 mice per group and are representative of 3 independent experiments with similar results. *P < .05 by Mann-Whitney U test, #P < .05 by ANOVA, and $P < .05 versus the intranasal vehicle challenge (after) by t test. ns, Not significantly different (C). BAL, bronchial alveolar lavage; e.c., epicutaneous sensitization by painting tape-stripped ear skin with papain; i.n., intranasal; Rag2−/−, Rag2-deficient mice, which lack adaptive immune cells. Journal of Allergy and Clinical Immunology 2018 141, 2271-2273.e7DOI: (10.1016/j.jaci.2017.11.035) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Crucial commitment of protease activity of low-dose papain inhalation to the onset of allergic airway inflammation in epicutaneously presensitized mice. Mice epicutaneously presensitized to papain were intranasally challenged with papain or E64-papain (3 μg). Bronchial alveolar lavage fluid (A-D), sera (B), and bronchial DLNs (E) were recovered and analyzed. A, Airway eosinophilia. B, Total and papain-specific IgE levels (before or after the intranasal challenge). C, Infiltration of TH2 cells, ST2+ TH2 cells, and ILC2s. D, TH2-attracting chemokines CCL17 and CCL22. E, Cytokine production in DLNs restimulated with E64-papain (Anitgen). Data are indicated as the mean ± SD of 4 to 6 mice (A-D) or 3 wells (E) per group and are representative of 2 or more independent experiments with similar results. Detection limits are indicated by dotted lines (E). *P < .05 by Mann-Whitney U test (A-D) and ANOVA (E), #P < .05 versus restimulation with medium by t test (E), and $P < .05 versus the intranasal papain challenge by t test (E, E64-papain intranasal). ns, Not significantly different (B). e.c., epicutaneous; i.n., intransal. Journal of Allergy and Clinical Immunology 2018 141, 2271-2273.e7DOI: (10.1016/j.jaci.2017.11.035) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Airway inflammation and papain-specific IgG1 responses induced by the inhalation of papain with a 4-day interval. A, Epicutaneously presensitized mice. B, Naive mice. Fig E1, A and B, are supplementary to Fig 1, A-C and D-F, respectively. Data shown in Fig 1, B and E, are included here for comparison. i.n., Intranasal. Data are indicated as the mean ± SD of 5 or 4 mice per group and are representative of 3 independent experiments with similar results. *P < .05 by the Mann-Whitney U test, #P < .05 by ANOVA, and $P < .05 versus the intraperitoneal vehicle challenge (After) by the t test. Even without epicutaneous presensitization, adaptive immune cells play an important role because Rag2−/− mice showed markedly less severe lung eosinophilia, similar to a 7-day interval model.E2 Journal of Allergy and Clinical Immunology 2018 141, 2271-2273.e7DOI: (10.1016/j.jaci.2017.11.035) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Airway inflammation and antibody responses induced by the inhalation of papain with an 8-day interval. A, Epicutaneously presensitized mice. B, Naive mice. Data are indicated as the mean ± SD of 5 mice per group. Data are representative of 3 independent experiments with similar results. *P < .05 by the Mann-Whitney U test, #P < .05 by ANOVA, and $P < .05 versus the intranasal vehicle challenge (After) by the t test. e.c., Epicutaneous; i.n., intransal. Journal of Allergy and Clinical Immunology 2018 141, 2271-2273.e7DOI: (10.1016/j.jaci.2017.11.035) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Enzymatic activity of inhaled papain is necessary for eosinophilic airway inflammation induced by the inhalation of papain with a 4-day interval in epicutaneously presensitized mice. A, Supplementary data for Fig 2, A and B. B, Mice epicutaneously sensitized to papain were intranasally challenged with papain or E-64-papain (10 or 30 μg). BAL, Bronchial alveolar lavage; e.c., epicutaneous; i.n., intransal. Data are indicated as the mean ± SD of 5 or 4 mice per group. Data are representative of 2 independent experiments with similar results. *P < .05 by the Mann-Whitney U test, #P < .05 by ANOVA, and $P < .05 versus the intranasal vehicle challenge (After) by the t test. Before: day 13. After: day 22. Journal of Allergy and Clinical Immunology 2018 141, 2271-2273.e7DOI: (10.1016/j.jaci.2017.11.035) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Covalent binding of E-64 to papain does not affect T-cell recall cytokine responses or antibody reactivity against T/B-cell epitope structures. Serum antibody binding (A) and cytokine production (B) in restimulated bronchial DLN cells from mice epicutaneously presensitized-intranasally challenged with papain. C, Cytokine production in restimulated bronchial DLN cells from mice intranasally administered papain. D, Responses of restimulated splenocytes from mice intraperitoneally immunized with papain. e.c., Epicutaneous; i.n., intransal; ip, intraperitoneal. Data are indicated as the mean ± SD of 3 wells per group. Data are representative of 2 independent experiments with similar results. Journal of Allergy and Clinical Immunology 2018 141, 2271-2273.e7DOI: (10.1016/j.jaci.2017.11.035) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Gating strategy in the flow cytometric analysis of TH2 cells. Cells contained in BALF were recovered 3 days after the last intranasal challenge (day 21) and analyzed with flow cytometry. A, Total live cells were gated on the basis of FSC and SSC and CD4-positive cells were then gated. B, CD4+CD62L−CD44Lo cells were gated and the expression of GATA3 and ST2 in the population was then analyzed. The CD4+CD62L−CD44LoGATA3+ population is indicated as TH2 and its ST2+ population is indicated as ST2+ TH2 in Fig 2, C. Representative data of 1 mice of each group are shown. i.n., Intranasal; FSC, forward scatter; SSC, side scatter. Journal of Allergy and Clinical Immunology 2018 141, 2271-2273.e7DOI: (10.1016/j.jaci.2017.11.035) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions