Abstract
Our body clock drives rhythms in the expression of genes that have a 24-h periodicity. The transcription factor BMAL1 is a crucial component of the molecular clock. A number of physiological processes, including immune function, are modulated by the circadian clock. Asthma, a disease with very strong clinical evidence demonstrating regulation by circadian variation, is of particular relevance to circadian control of immunity. Airway hypersensitivity and asthma attacks are more common at night in humans. The molecular basis for this is unknown, and there is no model of asthma in animals with genetic distortion of the molecular clock. We used mice lacking BMAL1 in myeloid cells (BMAL1-LysM-/-) to determine the role of BMAL1 in allergic asthma. Using the ovalbumin model of allergic asthma, we demonstrated markedly increased asthma features, such as increased lung inflammation, demonstrated by drastically higher numbers of eosinophils and increased IL-5 levels in the lung and serum, in BMAL1-LysM-/- mice. In vitro studies demonstrated increased proinflammatory chemokine and mannose receptor expression in IL-4- as well as LPS-treated macrophages from BMAL1-LysM-/- mice compared with wild-type controls. This suggests that Bmal1 is a potent negative regulator in myeloid cells in the context of allergic asthma. Our findings might explain the increase in asthma incidents during the night, when BMAL1 expression is low.