The circadian protein BMAL1 in myeloid cells is a negative regulator of allergic asthma.
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.
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; and.
Zbigniew
Z
Zasłona
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; and.
Sarah
S
Case
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; and.
James O
JO
Early
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; and.
Stephen J
SJ
Lalor
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; and.
Rachel M
RM
McLoughlin
Molecular and Cellular Therapeutics Department, Royal College of Surgeons in Ireland, Dublin, Ireland.
Anne M
AM
Curtis
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; and laoneill@tcd.ie.
Luke A J
LAJ
O'Neill
D056930:ARNTL Transcription Factors / Q000378:metabolism*; D000818:Animals; D001249:Asthma / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D002940:Circadian Rhythm; D004195:Disease Models, Animal; D004804:Eosinophils / Q000378:metabolism / Q000473:pathology; D006967:Hypersensitivity / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000378:metabolism*; D011014:Pneumonia / Q000150:complications / Q000378:metabolism / Q000473:pathology
D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D015415:Biomarkers; D018925:Chemokines; D018836:Inflammation Mediators; D015848:Interleukin-5
asthma; myeloid cells