Circadian clock gene Period2 regulates a time-of-day-dependent variation in cutaneous anaphylactic reaction

Background: IgE-mediated immediate-type skin reaction shows a diurnal rhythm, although the precise mechanisms remain uncertain. Period2 (Per2) is a key circadian gene that is essential for endogenous clockworks in mammals. Objective: This study investigated whether Per2 regulates a time-of-day- dependent variation in IgE-mediated immediate-type skin reaction. Methods: The kinetics of a passive cutaneous anaphylactic reaction were compared between wild-type mice and mice with a loss-of-function mutation of Per2 (mPer2 ^m/m mice). The effects of adrenalectomy, aging, and dexamethasone on the kinetics of a passive cutaneous anaphylactic reaction were also examined. In addition, the extent of IgE-mediated degranulation in bone marrow-derived mast cells (BMMCs) was compared between wild-type and mPer2^m/m mice. Results: A time-of-day-dependent variation in a passive cutaneous anaphylactic reaction observed in wild-type mice was absent in mPer2^m/m mice and in adrenalectomized and aged mice associated with the loss of rhythmic secretion of corticosterone. In addition, mPer2^m/m mice showed decreased sensitivity to the inhibitory effects of dexamethasone on the passive cutaneous anaphylactic reactions. IgE-mediated degranulation in BMMCs was comparable between wild-type and mPer2^m/m mice, but Per2 mutation decreased sensitivity to the inhibitory effects of dexamethasone on IgE-mediated degranulation in BMMCs. Conclusion: A circadian oscillator, Per2, regulates a time-of-day-dependent variation in a passive cutaneous anaphylactic reaction in mice. Per2 may do so by controlling the rhythmic secretion of glucocorticoid from adrenal glands and/or by gating the glucocorticoid responses of mast cells to certain times of the day (possibly when Per2 levels are high in mast cells).