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

Research output: Contribution to journalArticle

14 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 - Apr 1 2016
Externally publishedYes

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Circadian Clocks
Mast Cells
Immunoglobulin E
Basophils
Hypersensitivity
Dexamethasone
Glucocorticoids
Casein Kinase I
Period Circadian Proteins
IgE Receptors
Anti-Allergic Agents
Anaphylaxis
Corticosterone
Allergens
Down-Regulation
Bone Marrow
Pharmacology
Skin
Pharmaceutical Preparations
PF670462

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Nakamura, Y., Nakano, N., Ishimaru, K., Ando, N., Katoh, R., Suzuki-Inoue, K., ... 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

Inhibition of IgE-mediated allergic reactions by pharmacologically targeting the circadian clock. / Nakamura, Yuki; Nakano, Nobuhiro; Ishimaru, Kayoko; Ando, Noriko; Katoh, Ryohei; Suzuki-Inoue, Katsue; Koyanagki, Satoru; Ogawa, Hideoki; Okumura, Ko; Shibata, Shigenobu; Nakao, Atsuhito.

In: Journal of Allergy and Clinical Immunology, Vol. 137, No. 4, 01.04.2016, p. 1226-1235.

Research output: Contribution to journalArticle

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, vol. 137, no. 4, pp. 1226-1235. https://doi.org/10.1016/j.jaci.2015.08.052
Nakamura, Yuki ; Nakano, Nobuhiro ; Ishimaru, Kayoko ; Ando, Noriko ; Katoh, Ryohei ; Suzuki-Inoue, Katsue ; Koyanagki, Satoru ; Ogawa, Hideoki ; Okumura, Ko ; Shibata, Shigenobu ; Nakao, Atsuhito. / Inhibition of IgE-mediated allergic reactions by pharmacologically targeting the circadian clock. In: Journal of Allergy and Clinical Immunology. 2016 ; Vol. 137, No. 4. pp. 1226-1235.
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AU - Suzuki-Inoue, Katsue

AU - Koyanagki, Satoru

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N2 - 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.

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