Pharmacologic inhibition of Notch signaling suppresses food antigen–induced mucosal mast cell hyperplasia Asuka Honjo, MD, Nobuhiro Nakano, PhD, Susumu.

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Pharmacologic inhibition of Notch signaling suppresses food antigen–induced mucosal mast cell hyperplasia Asuka Honjo, MD, Nobuhiro Nakano, PhD, Susumu Yamazaki, MD, PhD, Mutsuko Hara, PhD, Koichiro Uchida, MD, PhD, Jiro Kitaura, MD, PhD, Chiharu Nishiyama, PhD, Hideo Yagita, PhD, Yoshikazu Ohtsuka, MD, PhD, Hideoki Ogawa, MD, PhD, Ko Okumura, MD, PhD, Toshiaki Shimizu, MD, PhD Journal of Allergy and Clinical Immunology Volume 139, Issue 3, Pages 987-996.e10 (March 2017) DOI: 10.1016/j.jaci.2016.05.046 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Notch signaling upregulates MMC marker expression in BMMCs. BMMCs were cultured for 6 days in the presence of IL-3 and SCF with the indicated Notch ligand–expressing CHO cells, control CHO cells, or TGF-β1. A, Expression of mRNA for the indicated proteases in BMMCs. B, Immunofluorescence staining for mMCP-1 in BMMCs. Red, mMCP-1; blue, 4′-6-diamidino-2-phenylindole dihydrochloride (DAPI). Scale bars = 10 μm. C, IgE-mediated release of mMCP-1 by BMMCs. D, Cellular histamine contents. E, Flow cytometric analysis of CD103 expression (bold line) on BMMCs (gated on FcεRI+c-Kit+). Negative control cells are plotted in a thin line. Values represent means ± SDs (n = 3-4). *P < .05 and **P < .005 between control mice and others. ##P < .005 between indicated treatments (Fig 1, A and D). ##P < .005 compared with IgE-treated control mice and **P < .005 compared with IgE + anti-IgE–treated control mice (Fig 1, C). Journal of Allergy and Clinical Immunology 2017 139, 987-996.e10DOI: (10.1016/j.jaci.2016.05.046) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Comparison of gene expression profiles by using microarray analysis. Hierarchical clustering and heat map of normalized intensity values for genes encoding adhesion molecules (A) and chemokine receptors (B) in naive BMMCs, BMMCs cultured with TGF-β1, BMMCs cocultured with Dll1-expressing CHO cells, and intestinal MMCs isolated from the small intestines of naive mice. Journal of Allergy and Clinical Immunology 2017 139, 987-996.e10DOI: (10.1016/j.jaci.2016.05.046) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Notch and IL-3 signaling act coordinately to upregulate MMC marker expression. BMMCs were cocultured with Dll1-expressing CHO cells or control CHO cells in the presence of IL-3, SCF, or both for 6 days. A, Expression of Mcpt1 mRNA. B, Flow cytometric analysis of CD103 expression (bold line) on BMMCs (gated on FcεRI+c-Kit+). Negative control cells are plotted in a thin line. C, Expression of Mcpt1 mRNA in BMMCs cocultured with Dll1-expressing CHO cells or control CHO cells in the presence or absence of either 10 μmol/L DAPT or IQDMA for 3 hours. Values represent means ± SDs (n = 3-4). **P < .005 between indicated treatments (Fig 3, A and C). ##P < .005 between each control and others (Fig 3, A). Journal of Allergy and Clinical Immunology 2017 139, 987-996.e10DOI: (10.1016/j.jaci.2016.05.046) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Expression of MMC markers is induced in BMMCs cocultured with mouse small intestinal LP cells through Notch signaling. A, Expression of the indicated Notch ligands on LP cells isolated from the mouse small intestine. B, BMMCs were cocultured with or without LP cells for 18 hours in the presence or absence of 10 μmol/L DAPT. Values represent means ± SDs (n = 3). **P < .005, #P < .05, and ##P < .005 between each control and others. Journal of Allergy and Clinical Immunology 2017 139, 987-996.e10DOI: (10.1016/j.jaci.2016.05.046) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Pharmacologic inhibition of Notch signaling attenuates food allergy. A, Experimental outline. B, Diarrhea occurrence in vehicle- or DAPT-treated mice after each intragastric OVA challenge (n = 9-10). C, Rectal temperature in vehicle- or DAPT-treated mice after the fourth intragastric OVA challenge (n = 3-4). D, Serum total IgE (left panel) and OVA-specific IgE (right panel) levels in mice after the fifth intragastric OVA challenge (n = 5). Values represent means ± SEMs. *P < .05 and **P < .005 between indicated treatments (Fig 5, C) or between OVA(−)/DAPT (−) and other treatments (Fig 5, D). n.s., Not significant. Journal of Allergy and Clinical Immunology 2017 139, 987-996.e10DOI: (10.1016/j.jaci.2016.05.046) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Pharmacologic inhibition of Notch signaling suppresses food antigen–induced mast cell hyperplasia. A, Toluidine blue staining of ascending colon (upper panels) and small intestine (lower panels) of mice after the fourth intragastric saline or OVA challenge. Scale bars = 50 μm. B, Mean number of mast cells of Fig 6, A, are expressed in numbers per square millimeter (n = 3-4). C, Expression of Mcpt1 mRNA in the ascending colon (left panel) and small intestine (right panel) of mice after the third and fifth intragastric saline or OVA challenge (n = 5). D, Serum mMCP-1 concentration of mice 5 hours after the fifth intragastric saline or OVA challenge (n = 5). Values represent means ± SEMs. *P < .05 and **P < .005 between indicated treatments (Fig 6, B and D). #P < .05 and ##P < .005 between OVA(−)/DAPT(−) and other treatments (Fig 6, B, C, and D). Journal of Allergy and Clinical Immunology 2017 139, 987-996.e10DOI: (10.1016/j.jaci.2016.05.046) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Expression of MMC-specific proteases is upregulated in BMMCs immediately after culturing in the presence of Dll1. Expression of mRNA for the indicated proteases in BMMCs cultured for 3 hours in the presence or absence of Dll1. Values represent means ± SDs (n = 4). **P < .005 between indicated treatments. Journal of Allergy and Clinical Immunology 2017 139, 987-996.e10DOI: (10.1016/j.jaci.2016.05.046) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Expression of MMC-specific proteases and other markers in BMMCs. BMMCs were cultured for 6 days in the presence of IL-3 and SCF with the indicated Notch ligand–expressing CHO cells, control CHO cells, or TGF-β1. A, Western blot analysis of BMMCs for the indicated protease. β-Actin was used as a loading control. B, Cellular heparin contents. *P < .05 between control and others. C and D, Flow cytometric analysis of TLR4/MD2 (Fig E2, C) and ST2 (Fig E2, D) expression (bold line) on BMMCs (gated on FcεRI+c-Kit+). Negative control cells are plotted in a thin line. Journal of Allergy and Clinical Immunology 2017 139, 987-996.e10DOI: (10.1016/j.jaci.2016.05.046) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Comparison of gene expression profiles by using microarray analysis. Hierarchical clustering and heat map of normalized intensity values of 35,240 transcripts in naive BMMCs, BMMCs cultured with TGF-β1, BMMCs cultured with Notch ligand Dll1, and intestinal MMCs isolated from the small intestines of naive mice. Journal of Allergy and Clinical Immunology 2017 139, 987-996.e10DOI: (10.1016/j.jaci.2016.05.046) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Effect of inhibitors on cell viability. BMMCs were cultured in the presence of 10 μmol/L DAPT, 10 μmol/L IQDMA, or vehicle (dimethyl sulfoxide) for the indicated time. Values represent means ± SDs (n = 4). *P < .05 and **P < .005 compared with vehicle. Journal of Allergy and Clinical Immunology 2017 139, 987-996.e10DOI: (10.1016/j.jaci.2016.05.046) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Administration of DAPT does not affect body weight of mice and serum IgE levels at day 23. A, Body weight change in the experimental period. DAPT or vehicle was administered intraperitoneally during the period indicated by the arrow. B, Serum total IgE (left panel) and OVA-specific IgE (right panel) levels in mice at day 23 (n = 5). Values represent means ± SEMs. *P < .05 and **P < .005 compared with OVA-unsensitized and DAPT-untreated mice (Fig E5, B). n.s., Not significant. Journal of Allergy and Clinical Immunology 2017 139, 987-996.e10DOI: (10.1016/j.jaci.2016.05.046) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 Administration of DAPT does not affect lymphocyte differentiation and functions. A and B, Flow cytometric analysis of CD4 and CD8 expression in thymocytes (Fig E6, A) and CD45R and CD3 expression (Fig E6, B, upper panels) and CD4 and CD8 expression (Fig E6, B, lower panels) in splenic cells of mice after the fifth intragastric saline or OVA challenge. C and D, Secretion of cytokines by MLN cells (Fig E6, C) and splenocytes (Fig E6, D), which were isolated from mice after the fifth intragastric saline or OVA challenge restimulated with 20 μg/mL OVA. Values represent means ± SEMs (n = 3). **P < .005 between indicated treatments. n.s., Not significant. Journal of Allergy and Clinical Immunology 2017 139, 987-996.e10DOI: (10.1016/j.jaci.2016.05.046) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E7 Administration of DAPT does not affect the number of CTMCs in the ear auricle. A, Toluidine blue staining of the ear auricle sections of mice after the fifth intragastric saline or OVA challenge. Scale bars = 50 μm. B, Mean number of mast cells of Fig E7, A, expressed in numbers per square millimeter (n = 3). Journal of Allergy and Clinical Immunology 2017 139, 987-996.e10DOI: (10.1016/j.jaci.2016.05.046) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E8 Degranulation of intestinal MMCs induced by intragastric OVA challenge is not affected by administration of DAPT. Flow cytometric analysis of the degranulation marker CD63 expression (bold line) on intestinal mast cells (gated on FcεRI+c-Kit+) in the small intestinal LP cells of mice 30 minutes after the fifth intragastric saline or OVA challenge. Negative control cells are plotted in a thin line. Journal of Allergy and Clinical Immunology 2017 139, 987-996.e10DOI: (10.1016/j.jaci.2016.05.046) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions