title: MicroRNA-33 Regulates the Innate Immune Response via ATP Binding Cassette Transporter-mediated Remodeling of Membrane Microdomains.
abstract: MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression by promoting degradation and/or repressing translation of specific target mRNAs. Several miRNAs have been identified that regulate the amplitude of the innate immune response by directly targeting Toll-like receptor (TLR) pathway members and/or cytokines. miR-33a and miR-33b (the latter present in primates but absent in rodents and lower species) are located in introns of the sterol regulatory element-binding protein (SREBP)-encoding genes and control cholesterol/lipid homeostasis in concert with their host gene products. These miRNAs regulate macrophage cholesterol by targeting the lipid efflux transporters ATP binding cassette (ABC)A1 and ABCG1. We and others have previously reported that Abca1(-/-) and Abcg1(-/-) macrophages have increased TLR proinflammatory responses due to augmented lipid raft cholesterol. Given this, we hypothesized that miR-33 would augment TLR signaling in macrophages via a raft cholesterol-dependent mechanism. Herein, we report that multiple TLR ligands down-regulate miR-33 in murine macrophages. In the case of lipopolysaccharide, this is a delayed, Toll/interleukin-1 receptor (TIR) domain-containing adapter-inducing interferon-β-dependent response that also down-regulates Srebf-2, the host gene for miR-33. miR-33 augments macrophage lipid rafts and enhances proinflammatory cytokine induction and NF-κB activation by LPS. This occurs through an ABCA1- and ABCG1-dependent mechanism and is reversible by interventions upon raft cholesterol and by ABC transporter-inducing liver X receptor agonists. Taken together, these findings extend the purview of miR-33, identifying it as an indirect regulator of innate immunity that mediates bidirectional cross-talk between lipid homeostasis and inflammation.
authors.affiliation: From the Immunity, Inflammation and Disease Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709.
authors.forename: Lihua
authors.initials: L
authors.lastname: Lai
authors.affiliation: From the Immunity, Inflammation and Disease Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Azzam
authors.affiliation: From the Immunity, Inflammation and Disease Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709.
authors.forename: Wan-Chi
authors.initials: WC
authors.lastname: Lin
authors.affiliation: From the Immunity, Inflammation and Disease Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709.
authors.forename: Prashant
authors.initials: P
authors.lastname: Rai
authors.affiliation: From the Immunity, Inflammation and Disease Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Lowe
authors.affiliation: From the Immunity, Inflammation and Disease Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709.
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Gabor
authors.affiliation: From the Immunity, Inflammation and Disease Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Madenspacher
authors.affiliation: From the Immunity, Inflammation and Disease Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709.
authors.forename: Jim J
authors.initials: JJ
authors.lastname: Aloor
authors.affiliation: Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157.
authors.forename: John S
authors.initials: JS
authors.lastname: Parks
authors.affiliation: Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Anders M
authors.initials: AM
authors.lastname: Näär
authors.affiliation: From the Immunity, Inflammation and Disease Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709, fesslerm@niehs.nih.gov.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Fessler
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000276:immunology*; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1 / Q000235:genetics / Q000276:immunology*; D000818:Animals; D007113:Immunity, Innate; D008264:Macrophages / Q000276:immunology*; D021962:Membrane Microdomains / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology*; D000067996:RAW 264.7 Cells; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000276:immunology
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D035683:MicroRNAs; D051782:Sterol Regulatory Element Binding Protein 2; C577833:Abca1 protein, mouse; C487540:ABCG1 protein, mouse; C550417:Mirn33 microRNA, mouse; C497391:Srebf2 protein, mouse
keywords: ABC transporter; cholesterol; lipid raft; macrophage; microRNA (miRNA); toll-like receptor (TLR)