Inhibition of IgE-mediated allergic reactions by pharmacologically targeting the circadian clock

Yuki Nakamura, Nobuhiro Nakano, Kayoko Ishimaru, Noriko Ando, Ryohei Katoh, Katsue Suzuki-Inoue, Satoru Koyanagki, Hideoki Ogawa, Ko Okumura, Shigenobu Shibata, Atsuhito Nakao

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    17 Citations (Scopus)

    Abstract

    Background The circadian clock temporally gates signaling through the high-affinity IgE receptor (FcϵRI) in mast cells, thereby generating a marked day/night variation in allergic reactions. Thus manipulation of the molecular clock in mast cells might have therapeutic potential for IgE-mediated allergic reactions. Objective We determined whether pharmacologically resetting the molecular clock in mast cells or basophils to times when FcϵRI signaling was reduced (ie, when core circadian protein period 2 [PER2] is upregulated) resulted in suppression of IgE-mediated allergic reactions. Methods We examined the effects of PF670462, a selective inhibitor of the key clock component casein kinase 1δ/ϵ, or glucocorticoid, both of which upregulated PER2 in mast cells, on IgE-mediated allergic reactions both in vitro and in vivo. Results PF670462 or corticosterone (or dexamethasone) suppressed IgE-mediated allergic reactions in mouse bone marrow-derived mast cells or basophils and passive cutaneous anaphylactic reactions in mice in association with increased PER2 levels in mast cells or basophils. PF670462 or dexamethasone also ameliorated allergic symptoms in a mouse model of allergic rhinitis and downregulated allergen-specific basophil reactivity in patients with allergic rhinitis. Conclusion Pharmacologically resetting the molecular clock in mast cells or basophils to times when FcϵRI signaling is reduced can inhibit IgE-mediated allergic reactions. The results suggest a new strategy for controlling IgE-mediated allergic diseases. Additionally, this study suggests a novel mechanism underlying the antiallergic actions of glucocorticoids that relies on the circadian clock, which might provide a novel insight into the pharmacology of this drug in allergic patients.

    Original languageEnglish
    Pages (from-to)1226-1235
    Number of pages10
    JournalJournal of Allergy and Clinical Immunology
    Volume137
    Issue number4
    DOIs
    Publication statusPublished - 2016 Apr 1

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    Keywords

    • allergy
    • basophils
    • Circadian clock
    • IgE
    • mast cells

    ASJC Scopus subject areas

    • Immunology and Allergy
    • Immunology

    Cite this

    Nakamura, Y., Nakano, N., Ishimaru, K., Ando, N., Katoh, R., Suzuki-Inoue, K., Koyanagki, S., Ogawa, H., Okumura, K., Shibata, S., & Nakao, A. (2016). Inhibition of IgE-mediated allergic reactions by pharmacologically targeting the circadian clock. Journal of Allergy and Clinical Immunology, 137(4), 1226-1235. https://doi.org/10.1016/j.jaci.2015.08.052