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

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• 作者：Yuki Nakamura ; PhD^a ; Nobuhiro Nakano ; PhD^b ; Kayoko Ishimaru^a ; Noriko Ando ; MD^c ; Ryohei Katoh ; MD ; PhD^d ; Katsue Suzuki-Inoue ; MD ; PhD^e ; Satoru Koyanagki ; PhD^f ; Hideoki Ogawa ; MD ; PhD^b ; Ko Okumura ; MD ; PhD^b ; Shigenobu Shibata ; PhD^g ; Atsuhito Nakao ; MD ; PhD^a ; ^b ; ^{anakao@yamanashi.ac.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Circadian clock ; mast cells ; basophils ; IgE ; allergy
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：137
• 期：4
• 页码：1226-1235
• 全文大小：2748 K

文摘

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.