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Circadian control of innate immunity in macrophages by miR-155 targeting Bmal1

  1. Luke A. J. O’Neilla,3
  1. aSchool of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland;
  2. bInstitute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
  3. cThe Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
  4. dDepartment of Genetics, Trinity College Dublin, Dublin 2, Ireland;
  5. eDepartment of Psychology, National University of Ireland, Maynooth, Ireland;
  6. fLaboratory of Lymphocyte Signaling and Development, Babraham Institute, Babraham Research Campus, Cambridge, Cambridgeshire, CB22 3AT, United Kingdom

  1. Edited by Joseph S. Takahashi, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, and approved April 28, 2015 (received for review January 21, 2015)

Significance

The 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-κB 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.

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.

Footnotes

  • ↵1To whom correspondence may be addressed. Email: acurtis{at}tcd.ie or garret{at}upenn.edu.

  • ↵2A.M.C., C.T.F., and G.Y. contributed equally to this work.

  • ↵3G.A.F. and L.A.J.O. contributed equally to this work.

  • Author contributions: A.M.C., C.T.F., G.Y., E.M.P.-M., M.P.R., A.N.C., E.V., G.A.F., and L.A.J.O. designed research; A.M.C., C.T.F., G.Y., E.M.P.-M., P.W., A.F.M., N.H.F., J.O.E., L.C., H.Z., C.X., S.S.G., A.N.C., and E.V. performed research; E.V. contributed new reagents/analytic tools; A.M.C., C.T.F., G.Y., E.M.P.-M., P.W., A.F.M., N.H.F., J.O.E., L.C., H.Z., C.X., K.H., M.P.R., and A.N.C. analyzed data; and A.M.C., C.T.F., G.A.F., and L.A.J.O. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1501327112/-/DCSupplemental.

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