Inhibition of IgE-Mediated Allergic Reaction By Pharmacologically Targeting the Circadian Clock

Abstract

Recently, we reported that the circadian clock temporally gates signaling via the high-affinity IgE receptor (FcepsilonRI) in mast cells, thereby generating a marked day–night variation in allergic reactions (JACI, 2014). We therefore hypothesized that pharmacologically resetting the molecular clock in mast cells to times when FcepsilonRI signaling is reduced (i.e., when core circadian protein PERIOD2 [PER2] is up-regulated) might inhibit IgE-mediated allergic reactions. In this study, we determined whether pharmacologically resetting the molecular clock in mast cells or basophils to times when FcepsilonRI signaling was reduced (i.e. when PER2 is up-regulated) resulted in suppression of IgE-mediated allergic reactions. We examined the effects of PF670462, a selective inhibitor of the key clock component casein kinase (CK)1delta/epsilon which up-regulated PER2 in mast cells, on IgE-mediated allergic reactions both in vitro and in vivo. PF670462 suppressed IgE-mediated allergic reactions in mouse bone marrow-derived mast cells or basophils, and the passive cutaneous anaphylactic (PCA) reaction in mice, in association with increased PER2 levels in mast cells or basophils. PF670462 ameliorated allergic symptoms in a mouse model of allergic rhinitis and down-regulated allergen-specific basophil reactivity in patients with allergic rhinitis. Pharmacologically resetting the molecular clock in mast cells or basophils to times when FcepsilonRI signaling is reduced can inhibit IgE-mediated allergic reactions. The results suggest a new strategy for controlling IgE-mediated allergic diseases.