Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 23, Pages 7231-7236Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1501327112
Keywords
inflammation; sepsis; circadian clock; miR-155; Bmal1
Categories
Funding
- European Research Council [268155_MicroInnate]
- Science Foundation Ireland [13/SIRG/2130]
- NIH [HL097800]
- European Community Seventh Framework Programme TIMER Project
- Science without Borders programme from Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, Brazil
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The response to an innate immune challenge is conditioned by the time of day, but the molecular basis for this remains unclear. In myeloid cells, there is a temporal regulation to induction by lipopolysaccharide (LPS) of the proinflammatory microRNA miR-155 that correlates inversely with levels of BMAL1. BMAL1 in the myeloid lineage inhibits activation of NF-kappa B and miR-155 induction and protects mice from LPS-induced sepsis. Bmal1 has two miR-155-binding sites in its 3'-UTR, and, in response to LPS, miR-155 binds to these two target sites, leading to suppression of Bmal1 mRNA and protein in mice and humans. miR-155 deletion perturbs circadian function, gives rise to a shorter circadian day, and ablates the circadian effect on cytokine responses to LPS. Thus, the molecular clock controls miR-155 induction that can repress BMAL1 directly. This leads to an innate immune response that is variably responsive to challenges across the circadian day.
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