Circadian activation of mast cells mediates the nocturnal response in allergic asthma

Abstract

Circadian rhythm is a conserved physiological feature of most organisms. Nocturnal symptoms are a common feature of allergic asthma in humans. Patients with nocturnal asthma show circadian variation of their pulmonary function and inflammation, but nocturnal asthmatic responses have not been documented in animal models. In this study we tested the hypotheses that house dust mite (HDM) allergen-sensitive nonhuman primates (NHP) manifest nocturnal symptoms, and whether intrinsic circadian activity in mast cells might underlie nocturnal asthma response. Dynamic compliance (C_dyn) and lung resistance (R_L) measured as indicators of bronchoconstriction in anesthetized NHP, at rest and following exposure to HDM allergen, methacholine, and albuterol, were highly correlated with 3 respiratory inductive plethysmography (RIP) parameters: Phase Angle of the rib cage and abdomen waveforms (PhAng), Baseline Effort Phase Relation (eBPRL) and Effort Phase Relation (ePhRL). 21 allergic subjects were challenged with HDM early in the morning, and eBPRL and ePhRL were monitored for 20 hours after provocation. 15 of the allergic subjects exhibited gradual increases in eBPRL and ePhRL between midnight and 6 AM, with peak activity at 4 AM. The results demonstrate that animals exhibiting acute responses to allergen exposure during the day also exhibit nocturnal airway obstruction, possibly resulting from bronchoconstriction. Mast cells are central effector cells in asthma, and were subsequently investigated for intrinsic circadian activity that could underlie nocturnal asthma responses. Bone marrow derived mast cells (BMMCs) were exposed to high concentrations of serum (serum shocked) to synchronize gene expression. Following serum shock, circadian genes (mPer2, Bmal1, Rev-erbá, and Dbp) exhibit oscillations for up to 72 hours. Likewise, the high affinity IgE receptor in BMMCs (FcåRIá) exhibited circadian expression. The fcer1a gene and FcåRIá protein following serum shock exhibited mean periods of 18.9 and 28.6 hours, respectively. Synchronized BMMCs stimulated with IgE/Ag at different circadian time display circadian rhythms in IL-13 mRNA. Taken together, synchronized BMMCs suggest an underlying circadian mechanism of nocturnal asthma in vitro.