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*

*この研究の対応する著者

研究成果: Article査読

28 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)1226-1235
ページ数10
ジャーナルJournal of Allergy and Clinical Immunology
137
4
DOI
出版ステータスPublished - 2016 4 1

ASJC Scopus subject areas

  • 免疫アレルギー学
  • 免疫学

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