title: The scavenger receptor MARCO modulates TLR-induced responses in dendritic cells.
abstract: The scavenger receptor MARCO mediates macrophage recognition and clearance of pathogens and their polyanionic ligands. However, recent studies demonstrate MARCO expression and function in dendritic cells, suggesting MARCO might serve to bridge innate and adaptive immunity. To gain additional insight into the role of MARCO in dendritic cell activation and function, we profiled transcriptomes of mouse splenic dendritic cells obtained from MARCO deficient mice and their wild type counterparts under resting and activating conditions. In silico analysis uncovered major alterations in gene expression in MARCO deficient dendritic cells resulting in dramatic alterations in key dendritic cell-specific pathways and functions. Specifically, changes in CD209, FCGR4 and Complement factors can have major consequences on DC-mediated innate responses. Notably, these perturbations were magnified following activation with the TLR-4 agonist lipopolysaccharide. To validate our in silico data, we challenged DC's with various agonists that recognize all mouse TLRs and assessed expression of a set of immune and inflammatory marker genes. This approach identified a differential contribution of MARCO to TLR activation and validated a major role for MARCO in mounting an inflammatory response. Together, our data demonstrate that MARCO differentially affects TLR-induced DC activation and suggest targeting of MARCO could lead to different outcomes that depend on the inflammatory context encountered by DC.
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Haydn T
authors.initials: HT
authors.lastname: Kissick
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Laura K
authors.initials: LK
authors.lastname: Dunn
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Sanjukta
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Morris
authors.initials: M
authors.lastname: Nechama
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, United States of America; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Lester
authors.initials: L
authors.lastname: Kobzik
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Mohamed S
authors.initials: MS
authors.lastname: Arredouani
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D017244:Complement Factor I / Q000378:metabolism; D003198:Computer Simulation; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008264:Macrophages / Q000276:immunology; D051379:Mice; D011956:Receptors, Cell Surface / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D011971:Receptors, Immunologic / Q000276:immunology* / Q000378:metabolism; D051116:Receptors, Scavenger / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000276:immunology*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D017244:Complement Factor I; D037181:Lectins, C-Type; D008024:Ligands; D008070:Lipopolysaccharides; D011956:Receptors, Cell Surface; D017452:Receptors, IgG; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D051197:Toll-Like Receptor 4; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C522404:Fcgr4 protein, mouse; C092228:Marco protein, mouse; C493487:Tlr4 protein, mouse
references.citation: Nat Rev Immunol. 2003 Feb;3(2):133-46
references.pmid: 12563297
references.citation: PLoS One. 2013 Jul 01;8(7):e67795
references.pmid: 23840879
references.citation: J Immunol. 1997 Mar 15;158(6):2723-30
references.pmid: 9058806
references.citation: Immunobiology. 2013 Oct;218(10):1217-26
references.pmid: 23669238
references.citation: Cell. 2011 Nov 11;147(4):853-67
references.pmid: 22078882
references.citation: Cell Mol Biol (Noisy-le-grand). 2004;50 Online Pub:OL657-65
references.pmid: 15588554
references.citation: J Immunol. 2005 Nov 1;175(9):6058-64
references.pmid: 16237101
references.citation: Cancer Immunol Immunother. 2010 Jun;59(6):875-84
references.pmid: 20054688
references.citation: Prostate. 2008 Oct 1;68(14):1517-30
references.pmid: 18668517
references.citation: Cancer Res. 2003 Apr 15;63(8):1860-4
references.pmid: 12702574
references.citation: Am J Respir Cell Mol Biol. 2007 Jan;36(1):43-52
references.pmid: 16902192
references.citation: J Immunol. 2007 May 1;178(9):5912-20
references.pmid: 17442975
references.citation: Am J Respir Cell Mol Biol. 2011 Nov;45(5):1036-44
references.pmid: 21562316
references.citation: Trends Immunol. 2013 Nov;34(11):548-55
references.pmid: 23954142
references.citation: J Exp Med. 2004 Jul 19;200(2):267-72
references.pmid: 15263032
references.citation: J Leukoc Biol. 2006 Oct;80(4):870-9
references.pmid: 16882874
references.citation: J Exp Med. 2004 Jan 5;199(1):81-90
references.pmid: 14699082
references.citation: Crit Rev Immunol. 2012;32(6):529-53
references.pmid: 23428227
references.citation: J Lipid Res. 2005 Jan;46(1):11-20
references.pmid: 15548472
references.citation: Blood. 2003 Oct 15;102(8):2940-7
references.pmid: 12842997
references.citation: Nat Immunol. 2005 Aug;6(8):769-76
references.pmid: 15995707
references.citation: Invest New Drugs. 2003 Feb;21(1):21-32
references.pmid: 12795527
references.citation: Science. 2009 Oct 9;326(5950):257-63
references.pmid: 19729616
references.citation: Nature. 2008 Mar 13;452(7184):234-8
references.pmid: 18305481
references.citation: PLoS Pathog. 2009 Jun;5(6):e1000474
references.pmid: 19521507
references.citation: Science. 1993 Apr 23;260(5107):547-9
references.pmid: 8097338
references.citation: J Leukoc Biol. 2009 Apr;85(4):595-605
references.pmid: 19112093
references.citation: J Immunol. 2003 Sep 15;171(6):2879-88
references.pmid: 12960310
references.citation: Nat Immunol. 2006 Feb;7(2):156-64
references.pmid: 16415873
references.citation: Blood. 2011 Jan 27;117(4):1319-28
references.pmid: 21098741
references.citation: J Cell Mol Med. 2008 Apr;12(2):690-700
references.pmid: 18419605
references.citation: J Clin Invest. 2007 Mar;117(3):757-64
references.pmid: 17332894
references.citation: J Lipid Res. 2009 Apr;50 Suppl:S282-6
references.pmid: 19074372
references.citation: Immunity. 1998 Jul;9(1):143-50
references.pmid: 9697844
references.citation: Nat Immunol. 2012 Jul 19;13(8):722-8
references.pmid: 22814351
references.citation: J Immunol. 2011 Oct 15;187(8):3911-7
references.pmid: 21969315
references.citation: J Cell Biol. 2007 Apr 23;177(2):265-75
references.pmid: 17452530