Inhibition of IgE-mediated allergic reactions by pharmacologically targeting the circadian clock Yuki Nakamura, PhD, Nobuhiro Nakano, PhD, Kayoko Ishimaru,

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Inhibition of IgE-mediated allergic reactions by pharmacologically targeting the circadian clock Yuki Nakamura, PhD, Nobuhiro Nakano, PhD, Kayoko Ishimaru, Noriko Ando, MD, Ryohei Katoh, MD, PhD, Katsue Suzuki-Inoue, MD, PhD, Satoru Koyanagki, PhD, Hideoki Ogawa, MD, PhD, Ko Okumura, MD, PhD, Shigenobu Shibata, PhD, Atsuhito Nakao, MD, PhD Journal of Allergy and Clinical Immunology Volume 137, Issue 4, Pages 1226-1235 (April 2016) DOI: 10.1016/j.jaci.2015.08.052 Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 PF670462 or corticosterone suppresses IgE-mediated allergic reactions in wild-type (WT), but not Clock-mutated, mast cells associated with increased PER2 levels. A, PER2LUC bioluminescence of BMMCs derived from Per2Luc knock-in mice (PER2LUC BMMCs) with or without Clock mutation (WT or ClockΔ19). PF670462 or corticosterone was added at 72 hours after the media change, as indicated by the arrows. B, IgE-mediated release of β-hexosaminidase in wild-type and Clock-mutated PER2LUC BMMCs (n = 6). C, IgE-dependent intracellular Ca2+ mobilization in wild-type and Clock-mutated PER2LUC BMMCs (n = 4). D, IgE-dependent total tyrosine phosphorylation levels in wild-type and Clock-mutated PER2LUC BMMCs. Upper panels, Representative pictures; lower panels, quantitative analysis. E, FcεRIα levels on wild-type and Clock-mutated PER2LUC BMMCs (n = 4). F, FcεRIα levels on peritoneal mast cells (n = 10). CORT, Corticosterone; MFI, mean fluorescence intensity. Values represent means ± SDs. *P < .05. Journal of Allergy and Clinical Immunology 2016 137, 1226-1235DOI: (10.1016/j.jaci.2015.08.052) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 PF670462 suppresses PCA reactions associated with increased PER2 levels in mast cells. A, Representative pictures of in vivo imaging of mast cell–deficient mice reconstituted with subcutaneous injections of BMMCs derived from Per2Luc knock-in mice with or without Clock mutation (PER2LUC BMMCs or ClockΔ19 PER2LUC BMMCs). Mice were treated with PF670462 (50 mg/kg administered intraperitoneally) or vehicle at ZT4 (10 am), and the pictures were taken at ZT8 (2 pm). B, Quantitative analysis of the data in Fig 2, A (n = 5). C, Representative pictures of the skin color reactions at ZT8 in mast cell–deficient mice reconstituted with subcutaneous injections of PER2LUC BMMCs or ClockΔ19 PER2LUC BMMCs (upper panels) and digitized images used for density value evaluations (lower panels). Reconstituted mice were treated with PF670462 (50 mg/kg administered intraperitoneally) or vehicle at ZT4, and PCA reactions were induced at ZT8. D, Quantitative analysis of the data in Fig 2, C (n = 5). E, Serum monocyte chemoattractant protein 1 (MCP-1; CCL2) levels 30 minutes after induction of PCA reactions, as described in Fig 2, C (n = 5). F, Serum corticosterone and total IgE levels at ZT8, as described in Fig 2, C (n = 5). Values represent means ± SDs. *P < .05. Journal of Allergy and Clinical Immunology 2016 137, 1226-1235DOI: (10.1016/j.jaci.2015.08.052) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 DEX suppresses the PCA reaction associated with increased PER2 levels in mast cells. A, Representative pictures of in vivo imaging of mast cell–deficient mice reconstituted with subcutaneous injections of BMMCs derived from Per2Luc knock-in mice with or without Clock mutation (PER2LUC BMMCs or ClockΔ19 PER2LUC BMMCs). The mice were treated with DEX (50 mg/kg administered intraperitoneally) or vehicle at ZT4 (AM10:00), and the pictures were taken at ZT8 (PM 2:00). B, Quantitative analysis of the data in Fig 3, A (n = 3-4). C, Representative pictures of the skin color reactions at ZT8 in mast cell–deficient mice reconstituted with subcutaneous injections of PER2LUC BMMCs or ClockΔ19 PER2LUC BMMCs (upper panels) and digitalized images for the density value evaluations (lower panels). Reconstituted mice were treated with DEX (50 mg/kg administered intraperitoneally) or vehicle at ZT4, and PCA reactions were induced at ZT8. D, Quantitative analysis of the data in Fig 3, C (n = 3-4). E, Serum monocyte chemoattractant protein 1 (MCP-1; CCL2) levels 30 minutes after induction of PCA reactions, as described in Fig 3, C (n = 3-4). WT, Wild-type. Values represent means ± SDs. *P < .05. Journal of Allergy and Clinical Immunology 2016 137, 1226-1235DOI: (10.1016/j.jaci.2015.08.052) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 PF670462 suppresses IgE-mediated allergic symptoms in an allergic rhinitis (AR) model. A, The frequency of nasal rubbing or sneezing was counted for a 10-minute period after the last intranasal challenge with OVA (n = 5-6). B, OVA-specific IgE levels in the serum of unsensitized (normal) or sensitized (AR model) mice (n = 5-6). Values represent means ± SDs. *P < .05. Journal of Allergy and Clinical Immunology 2016 137, 1226-1235DOI: (10.1016/j.jaci.2015.08.052) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 PF670462 or corticosterone suppresses IgE-mediated allergic reactions in mouse and human basophils. A, PER2LUC bioluminescence of bone marrow–derived basophils derived from Per2Luc knock-in mice (PER2LUC BM basophils) with or without Clock mutation (WT or ClockΔ19). PF670462 or corticosterone (CORT) was added at 72 hours after the media change, as indicated by arrows. B, IgE-mediated production of histamine and IL-4 in wild-type or Clock-mutated PER2LUC BM basophils (n = 4-6). C, FcεRIα levels on wild-type and Clock-mutated PER2LUC BM basophils (n = 4). MFI, Mean fluorescence intensity. D, IgE-mediated histamine or IL-4 production in basophils from peripheral blood of healthy volunteers pretreated with PF670462 or PF4800567 for 15 or 240 minutes (n = 4). E, FcεRIα levels on basophils from peripheral blood of healthy volunteers pretreated with PF670462 or PF4800567 for 15 or 240 minutes (n = 3). F, CD203c expression on basophils after stimulation with JCP. Basophils were pretreated with 10 μmol/L PF670462 or PF4800567 for 15 (n = 5) or 240 minutes (n = 16) before JCP stimulation. Left panels, Representative data; right panels, quantitative data. See also Table E1. CORT, Corticosterone; CRTH2, chemoattractant receptor–homologous molecule expressed on TH2 lymphocytes; WT, wild-type. Values represent means ± SDs. *P < .05. Journal of Allergy and Clinical Immunology 2016 137, 1226-1235DOI: (10.1016/j.jaci.2015.08.052) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions