期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：23
页码：7231-7236
DOI：10.1073/pnas.1501327112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe circadian clock allows an organism to anticipate daily changes imposed by the environment. The response to LPS is altered depending on time of day; however, the molecular mechanisms underlying this are unclear. We find that the clock in myeloid cells plays a role in LPS-induced sepsis by altering NF-{kappa}B activity and the induction of the microRNA miR-155. LPS causes the repression of BMAL1 via the targeting of miR-155 to two seed sequences in the 3'-untranslated region of Bmal1. Lack of miR-155 has profound effects on circadian function and circadian induction of cytokines by LPS. Thus, the molecular clock is using miR-155 as an important regulatory component to control inflammation variably across the circadian day in myeloid cells. 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.
