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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:137

Article

Nakamura, Yuki¹  Nakano, Nobuhiro⁵  Ishimaru, Kayoko¹  Ando, Noriko²  Katoh, Ryohei³  Suzuki-Inoue, Katsue⁴  Koyanagki, Satoru⁶  Ogawa, Hideoki⁵  Okumura, Ko⁵  Shibata, Shigenobu⁷  Nakao, Atsuhito^1,5 

[1] Univ Yamanashi, Fac Med, Dept Immunol, 1110 Shimokato, Yamanashi 4093898, Japan

[2] Univ Yamanashi, Fac Med, Dept Dermatol, 1110 Shimokato, Yamanashi 4093898, Japan

[3] Univ Yamanashi, Fac Med, Dept Pathol, 1110 Shimokato, Yamanashi 4093898, Japan

[4] Univ Yamanashi, Fac Med, Dept Clin & Lab Med, 1110 Shimokato, Yamanashi 4093898, Japan

[5] Juntendo Univ, Sch Med, Atopy Res Ctr, Tokyo 113, Japan

[6] Grad Sch Pharmaceut Sci, Dept Pharmaceut, Fukuoka, Japan

[7] Waseda Univ, Sch Adv Sci & Engn, Dept Physiol & Pharmacol, Tokyo, Japan

关键词: Circadian clock;    mast cells;    basophils;    IgE;    allergy;   

DOI  :  10.1016/j.jaci.2015.08.052

来源: Elsevier

【 摘 要 】

Background: The circadian clock temporally gates signaling through the high-affinity IgE receptor (Fc epsilon RI) 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 FceRI 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 1 delta/epsilon, 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 Fc epsilon RI 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.

【 授权许可】

Free