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

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.

• Authors: Yuki Nakamura, Nobuhiro Nakano, Kayoko Ishimaru, Noriko Ando, Ryohei Katoh, Katsue Suzuki-Inoue, Satoru Koyanagki, Hideoki Ogawa, Ko Okumura, Shigenobu Shibata, Atsuhito Nakao
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 137 Issue 4 Pg. 1226-1235 (Apr 2016) ISSN: 1097-6825 [Electronic] United States
• PMID: 26559325 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers
• Imidazoles
• Immunologic Factors
• Per2 protein, mouse
• Period Circadian Proteins
• Pyrimidines
• Receptors, IgE
• PF-670462
• Casein Kinase 1 epsilon
• Casein Kinase Idelta

Topics

• Anaphylaxis (drug therapy, immunology)
• Animals
• Basophils (drug effects, immunology, metabolism)
• Biomarkers (metabolism)
• Casein Kinase 1 epsilon (antagonists & inhibitors)
• Casein Kinase Idelta (antagonists & inhibitors)
• Circadian Clocks (drug effects, immunology)
• Imidazoles (pharmacology, therapeutic use)
• Immunologic Factors (pharmacology, therapeutic use)
• Mast Cells (drug effects, immunology, metabolism)
• Mice
• Period Circadian Proteins (metabolism)
• Pyrimidines (pharmacology, therapeutic use)
• Receptors, IgE (metabolism)
• Rhinitis, Allergic (drug therapy, immunology)
• Treatment Outcome