1. The circadian regulator BMAL1 programmes responses to parasitic worm infection via a dendritic cell clock
- Author
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Hopwood, TW, Hall, S, Begley, N, Forman, R, Brown, S, Vonslow, R, Saer, B, Little, MC, Murphy, EA, Hurst, RJ, Ray, DW, Macdonald, AS, Brass, A, Bechtold, DA, Gibbs, JE, Loudon, AS, and Else, KJ
- Subjects
Male ,Mice, Knockout ,ResearchInstitutes_Networks_Beacons/MICRA ,T-Lymphocytes ,lcsh:R ,ARNTL Transcription Factors ,lcsh:Medicine ,Dendritic Cells ,Article ,Circadian Rhythm ,Mice, Inbred C57BL ,Mice ,Th2 Cells ,Trichuris ,Manchester Institute for Collaborative Research on Ageing ,Animals ,lcsh:Q ,Lymph Nodes ,Trichuriasis ,lcsh:Science ,Cells, Cultured - Abstract
Resistance to the intestinal parasitic helminth Trichuris muris requires T-helper 2 (TH2) cellular and associated IgG1 responses, with expulsion typically taking up to 4 weeks in mice. Here, we show that the time-of-day of the initial infection affects efficiency of worm expulsion, with strong TH2 bias and early expulsion in morning-infected mice. Conversely, mice infected at the start of the night show delayed resistance to infection, and this is associated with feeding-driven metabolic cues, such that feeding restriction to the day-time in normally nocturnal-feeding mice disrupts parasitic expulsion kinetics. We deleted the circadian regulator BMAL1 in antigen-presenting dendritic cells (DCs) in vivo and found a loss of time-of-day dependency of helminth expulsion. RNAseq analyses revealed that IL-12 responses to worm antigen by circadian-synchronised DCs were dependent on BMAL1. Therefore, we find that circadian machinery in DCs contributes to the TH1/TH2 balance, and that environmental, or genetic perturbation of the DC clock results in altered parasite expulsion kinetics.
- Published
- 2018