title: MicroRNA-17/20a/106a modulate macrophage inflammatory responses through targeting signal-regulatory protein α.
abstract: BACKGROUND
  Signal-regulatory protein α (SIRPα) is an essential signaling molecule that modulates leukocyte inflammatory responses. However, the regulation of selective SIRPα synthesis and its dynamic changes in leukocytes under inflammatory stimulation remain incompletely understood.
  
  
  OBJECTIVE
  We sought to identify the microRNAs (miRNAs) that posttranscriptionally regulate SIRPα synthesis and their roles in modulating macrophage inflammatory responses.
  
  
  METHODS
  SIRPα was induced in SIRPα-negative promyelocytic cells by retinoic acid or phorbol 12-myristate 13-acetate, and the differential expression of miRNAs was assessed by means of microarray and quantitative RT-PCR assays. The roles of identified miRNAs in controlling SIRPα synthesis in leukocytes and leukocyte inflammatory responses were determined.
  
  
  RESULTS
  We identified SIRPα as a common target gene of miR-17, miR-20a, and miR-106a. During SIRPα induction, levels of these 3 miRNAs were all reduced, and their downregulation by retinoic acid or phorbol 12-myristate 13-acetate occurred through suppression of the c-Myc signaling pathway. All miR-17, miR-20a, and miR-106a specifically bound to the same seed sequence within the SIRPα 3' untranslated region and correlated inversely with SIRPα protein levels in various cells. In macrophages upregulation of miR-17, miR-20a, and miR-106a by LPS served as the mechanism underlying LPS-induced SIRPα reduction and macrophage activation. Both in vitro and in vivo assays demonstrate that miR-17, miR-20a, and miR-106a regulate macrophage infiltration, phagocytosis, and proinflammatory cytokine secretion through targeting SIRPα.
  
  
  CONCLUSIONS
  These findings demonstrate for the first time that miR-17, miR-20a, and miR-106a regulate SIRPα synthesis and SIRPα-mediated macrophage inflammatory responses in a redundant fashion, providing a novel pathway in which a panel of miRNAs can modulate immune polarization through regulation of macrophage activation.
authors.affiliation: Research Institute of Nephrology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Dihan
authors.initials: D
authors.lastname: Zhu
authors.forename: Chaoyun
authors.initials: C
authors.lastname: Pan
authors.forename: Limin
authors.initials: L
authors.lastname: Li
authors.forename: Zhen
authors.initials: Z
authors.lastname: Bian
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Lv
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Donghai
authors.initials: D
authors.lastname: Li
authors.forename: Hongwei
authors.initials: H
authors.lastname: Gu
authors.forename: Chen-Yu
authors.initials: CY
authors.lastname: Zhang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Ke
authors.initials: K
authors.lastname: Zen
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005786:Gene Expression Regulation; D018922:HL-60 Cells; D006801:Humans; D007249:Inflammation / Q000276:immunology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020298:U937 Cells
chemical_list: D000943:Antigens, Differentiation; C542541:MIRN106 microRNA, human; C524941:MIRN17 microRNA, human; C534451:MIRN20a microRNA, human; D035683:MicroRNAs; D011971:Receptors, Immunologic; C501920:SIRPA protein, human
keywords: ASO; Antisense oligonucleotide; FITC; Fluorescein isothiocyanate; GAPDH; Galactosylated low-molecular-weight chitosan; Glyceraldehyde-3-phosphate dehydrogenase; ITIM; Immunoreceptor tyrosine-based inhibitory motif; Micro RNA; NO; Nitric oxide; Normal control RNA; PEI; Phorbol 12-myristate 13-acetate; Pre-normal control RNA; RA; Retinoic acid; SIRPα; SP-A; SP-D; Signal-regulatory protein α; Surfactant protein A; Surfactant protein D; TPA; UTR; Untranslated region; inflammatory response; macrophage; miRNA; microRNA; ncRNA; pre-ncRNA
references.citation: Cell Signal. 2012 Jun;24(6):1185-94
references.pmid: 22330073
references.citation: J Immunol. 2005 Dec 15;175(12):7781-7
references.pmid: 16339510
references.citation: Mol Cell Biol. 1996 Dec;16(12):6887-99
references.pmid: 8943344
references.citation: J Mol Biol. 2007 Jan 19;365(3):680-93
references.pmid: 17070842
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):12885-90
references.pmid: 18728182
references.citation: Blood. 1993 Jul 15;82(2):625-32
references.pmid: 8101106
references.citation: Cell. 2003 Oct 3;115(1):13-23
references.pmid: 14531999
references.citation: PLoS One. 2008 Sep 29;3(9):e3291
references.pmid: 18820737
references.citation: Nat Genet. 2008 Jan;40(1):43-50
references.pmid: 18066065
references.citation: Gut. 2010 Apr;59(4):470-9
references.pmid: 19951904
references.citation: Cell. 2004 Jan 23;116(2):281-97
references.pmid: 14744438
references.citation: J Biol Chem. 2005 Nov 25;280(47):39294-301
references.pmid: 16159885
references.citation: Dev Biol. 2009 Feb 15;326(2):431-43
references.pmid: 19073166
references.citation: Biochem Biophys Res Commun. 1997 Oct 20;239(2):483-7
references.pmid: 9344856
references.citation: J Immunol. 2002 Jun 1;168(11):5832-9
references.pmid: 12023387
references.citation: Immunity. 2002 Nov;17(5):583-91
references.pmid: 12433365
references.citation: J Immunol. 2006 Sep 1;177(5):3123-32
references.pmid: 16920950
references.citation: J Exp Med. 2007 Oct 29;204(11):2719-31
references.pmid: 17954568
references.citation: J Periodontal Res. 2012 Dec;47(6):719-28
references.pmid: 22571166
references.citation: Nat Rev Immunol. 2006 Jun;6(6):457-64
references.pmid: 16691243
references.citation: J Biol Chem. 2000 Sep 8;275(36):28222-9
references.pmid: 10842184
references.citation: Mol Cell Biol. 1999 Apr;19(4):3205-15
references.pmid: 10082587
references.citation: Cancer Sci. 2009 Oct;100(10):1786-93
references.pmid: 19622105
references.citation: Cancer Res. 2008 Jul 15;68(14):5540-5
references.pmid: 18632605
references.citation: Nature. 1997 Mar 13;386(6621):181-6
references.pmid: 9062191
references.citation: Am J Respir Crit Care Med. 2008 Jul 15;178(2):158-67
references.pmid: 18420961
references.citation: Nature. 2005 Jun 9;435(7043):839-43
references.pmid: 15944709
references.citation: J Cell Sci. 2006 Jul 1;119(Pt 13):2749-57
references.pmid: 16772332
references.citation: J Biol Chem. 2002 Mar 22;277(12):10028-36
references.pmid: 11792697
references.citation: Dev Biol. 2007 Oct 15;310(2):442-53
references.pmid: 17765889
references.citation: Nature. 2004 Sep 16;431(7006):350-5
references.pmid: 15372042
references.citation: J Biol Chem. 1998 Aug 28;273(35):22719-28
references.pmid: 9712903
references.citation: Blood. 2006 Jan 1;107(1):341-8
references.pmid: 16141346
references.citation: Science. 1996 Nov 1;274(5288):795-8
references.pmid: 8864123
references.citation: J Biol Chem. 1998 Apr 10;273(15):9234-42
references.pmid: 9535915
references.citation: Blood. 1992 Feb 1;79(3):627-33
references.pmid: 1732008
references.citation: J Immunol. 2000 Jan 1;164(1):427-35
references.pmid: 10605039
references.citation: J Cell Sci. 2001 Jun;114(Pt 11):2187-98
references.pmid: 11493654
references.citation: J Exp Med. 2003 Dec 1;198(11):1677-88
references.pmid: 14657220
references.citation: Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3978-82
references.pmid: 7732016
references.citation: Trends Cell Biol. 2009 Feb;19(2):72-80
references.pmid: 19144521