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The Use of Mouse Splenocytes to Assess Pathogen-associated Molecular Pattern Influence on Clock Gene Expression
Published on: July 24, 2018
Circadian control of innate immunity in macrophages by miR-155 targeting Bmal1
Anne M Curtis1, Caio T Fagundes2, Guangrui Yang3
1School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; acurtis@tcd.ie garret@upenn.edu.
Abstract:
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-κB 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.
Insights
The circadian clock regulates the immune response by controlling microRNA miR-155 induction, which directly represses BMAL1. This molecular mechanism explains how immune responses vary with the time of day.
Area of Science:
- Immunology
- Chronobiology
- Molecular Biology
Background:
- Innate immune responses exhibit daily variations, but the underlying molecular mechanisms are not fully understood.
- Lipopolysaccharide (LPS) challenge in myeloid cells reveals temporal regulation of microRNA miR-155 induction, inversely correlated with BMAL1 levels.
Purpose of the Study:
- To elucidate the molecular basis for the time-of-day regulation of innate immune responses.
- To investigate the role of BMAL1 and miR-155 in the circadian control of immune challenges.
Main Methods:
- Investigated the temporal regulation of miR-155 induction by LPS in myeloid cells.
- Analyzed the interaction between BMAL1 and miR-155, including miR-155 binding sites in Bmal1 3'-UTR.
- Assessed the impact of miR-155 deletion on circadian function and LPS-induced cytokine responses in mice.
Main Results:
- BMAL1 in myeloid cells inhibits NF-κB activation and miR-155 induction, protecting against LPS-induced sepsis.
- miR-155 directly binds to Bmal1 mRNA, suppressing its expression in both mice and humans.
- Deletion of miR-155 disrupts circadian rhythmicity and abolishes the circadian influence on LPS-induced cytokine responses.
Conclusions:
- The molecular clock controls miR-155 induction, which in turn directly represses BMAL1.
- This feedback loop results in a circadian rhythm in the innate immune response, affecting its sensitivity to challenges throughout the day.
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