Loss of the molecular clock in myeloid cells exacerbates T cell-mediated CNS autoimmune disease

Caroline E. Sutton, Conor M. Finlay, Mathilde Raverdeau, James O. Early, Joseph DeCourcey, Zbigniew Zaslona, Luke A. J. O’Neill, Kingston H. G. Mills () and Annie M. Curtis ()
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Caroline E. Sutton: Immune Regulation Research Group, Trinity Biomedical Sciences Institute, Trinity College Dublin
Conor M. Finlay: Immune Regulation Research Group, Trinity Biomedical Sciences Institute, Trinity College Dublin
Mathilde Raverdeau: Immune Regulation Research Group, Trinity Biomedical Sciences Institute, Trinity College Dublin
James O. Early: Inflammatory Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin
Joseph DeCourcey: Immune Regulation Research Group, Trinity Biomedical Sciences Institute, Trinity College Dublin
Zbigniew Zaslona: Inflammatory Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin
Luke A. J. O’Neill: Inflammatory Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin
Kingston H. G. Mills: Immune Regulation Research Group, Trinity Biomedical Sciences Institute, Trinity College Dublin
Annie M. Curtis: Royal College of Surgeons in Ireland (RCSI)

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract The transcription factor BMAL1 is a core component of the molecular clock, regulating biological pathways that drive 24 h (circadian) rhythms in behaviour and physiology. The molecular clock has a profound influence on innate immune function, and circadian disruption is linked with increased incidence of multiple sclerosis (MS). However, the mechanisms underlying this association are unknown. Here we show that BMAL1 and time-of-day regulate the accumulation and activation of various immune cells in a CNS autoimmune disease model, experimental autoimmune encephalomyelitis (EAE). In myeloid cells, BMAL1 maintains anti-inflammatory responses and reduces T cell polarization. Loss of myeloid BMAL1 or midday immunizations to induce EAE create an inflammatory environment in the CNS through expansion and infiltration of IL-1β-secreting CD11b+Ly6Chi monocytes, resulting in increased pathogenic IL-17+/IFN-γ+ T cells. These findings demonstrate the importance of the molecular clock in modulating innate and adaptive immune crosstalk under autoimmune conditions.

Date: 2017
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DOI: 10.1038/s41467-017-02111-0

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