Nasal solitary chemosensory cells govern daily rhythm in mouse model of allergic rhinitis

Abstract

BackgroundWhile the daily rhythm of allergic rhinitis (AR) has long been recognized, the molecular mechanism underlying this phenomenon remains enigmatic. ObjectiveWe aim to investigate the role of circadian clock in AR development and to clarify the mechanism by which the daily rhythm of AR is generated. MethodsAR was induced in mice using the ovalbumin method. Toluidine blue staining, LC-MS/MS analysis, qPCR, and immunoblotting were performed with AR and control mice. ResultsOvalbumin-induced AR is diurnally rhythmic and associated with clock gene disruption in nasal mucosa. In particular, Rev-erbα is generally down-regulated, and its rhythm retained but with a near 12-h phase shift. Furthermore, global knockout of the core clock gene Bmal1 or Rev-erbα increases the susceptibility of mice to AR and blunts AR rhythmicity. Importantly, nasal SCCs (solitary chemosensory cells) are rhythmically activated, and inhibition of the SCC pathway leads to attenuated AR and a loss of its rhythm. Moreover, rhythmic activation of SCCs is accounted for by diurnal expression of ChAT (an enzyme responsible for the synthesis of acetylcholine) and temporal generation of the neurotransmitter acetylcholine. Mechanistically, REV-ERBα trans-represses Chat through direct binding to a specific response element, generating a diurnal oscillation in this target gene. ConclusionThese findings identify SCCs, under the control of REV-ERBα, as a driver of AR rhythmicity, and suggest targeting SCCs as a new avenue for AR management.