title: Circadian control of innate immunity in macrophages by miR-155 targeting Bmal1.
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.
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; acurtis@tcd.ie garret@upenn.edu.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Curtis
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland;
authors.forename: Caio T
authors.initials: CT
authors.lastname: Fagundes
authors.affiliation: Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Guangrui
authors.identifier: http://orcid.org/0000-0002-8310-8257
authors.initials: G
authors.lastname: Yang
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland;
authors.forename: Eva M
authors.initials: EM
authors.lastname: Palsson-McDermott
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland;
authors.forename: Paulina
authors.initials: P
authors.lastname: Wochal
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland;
authors.forename: Anne F
authors.initials: AF
authors.lastname: McGettrick
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland;
authors.forename: Niamh H
authors.initials: NH
authors.lastname: Foley
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland;
authors.forename: James O
authors.initials: JO
authors.lastname: Early
authors.affiliation: Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Lihong
authors.initials: L
authors.lastname: Chen
authors.affiliation: The Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Hanrui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: The Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Chenyi
authors.initials: C
authors.lastname: Xue
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland;
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Geiger
authors.affiliation: Department of Genetics, Trinity College Dublin, Dublin 2, Ireland;
authors.forename: Karsten
authors.initials: K
authors.lastname: Hokamp
authors.affiliation: The Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Muredach P
authors.initials: MP
authors.lastname: Reilly
authors.affiliation: Department of Psychology, National University of Ireland, Maynooth, Ireland;
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Coogan
authors.affiliation: Laboratory of Lymphocyte Signaling and Development, Babraham Institute, Babraham Research Campus, Cambridge, Cambridgeshire, CB22 3AT, United Kingdom.
authors.forename: Elena
authors.initials: E
authors.lastname: Vigorito
authors.affiliation: Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; acurtis@tcd.ie garret@upenn.edu.
authors.forename: Garret A
authors.initials: GA
authors.lastname: FitzGerald
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland;
authors.forename: Luke A J
authors.initials: LA
authors.lastname: O'Neill
mesh_terms: D020413:3' Untranslated Regions; D056930:ARNTL Transcription Factors / Q000235:genetics / Q000502:physiology*; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002940:Circadian Rhythm; D016207:Cytokines / Q000096:biosynthesis; D007113:Immunity, Innate; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D016207:Cytokines; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D016328:NF-kappa B
keywords: Bmal1; circadian clock; inflammation; miR-155; sepsis