title: Impaired resolution of inflammation in the Endoglin heterozygous mouse model of chronic colitis.
abstract: Endoglin is a coreceptor of the TGF-β superfamily predominantly expressed on the vascular endothelium and selective subsets of immune cells. We previously demonstrated that Endoglin heterozygous (Eng (+/-)) mice subjected to dextran sulfate sodium (DSS) developed persistent gut inflammation and pathological angiogenesis. We now report that colitic Eng (+/-) mice have low colonic levels of active TGF-β1, which was associated with reduced expression of thrombospondin-1, an angiostatic factor known to activate TGF-β1. We also demonstrate dysregulated expression of BMPER and follistatin, which are extracellular regulators of the TGF-β superfamily that modulate angiogenesis and inflammation. Heightened colonic levels of the neutrophil chemoattractant and proangiogenic factor, CXCL1, were also observed in DSS-treated Eng (+/-) mice. Interestingly, despite increased macrophage and neutrophil infiltration, a gut-specific reduction in expression of the key phagocytic respiratory burst enzymes, NADPH oxidase 2 (Nox-2) and myeloperoxidase, was seen in Eng (+/-) mice undergoing persistent inflammation. Taken together, these findings suggest that endoglin is required for TGF-β superfamily mediated resolution of inflammation and fully functional myeloid cells.
authors.affiliation: Molecular Structure and Function Program, The Hospital for Sick Children, Toronto, ON, Canada M5G 0A4 ; Department of Immunology, University of Toronto, Toronto, ON, Canada M5S 1A8.
authors.forename: Madonna R
authors.initials: MR
authors.lastname: Peter
authors.affiliation: Molecular Structure and Function Program, The Hospital for Sick Children, Toronto, ON, Canada M5G 0A4 ; Keenan Research Centre in Li Ka Shing Knowledge Institute, St. Michael's Hospital, 209 Victoria Street, Toronto, ON, Canada M5B 1T8.
authors.forename: Mirjana
authors.identifier: 0000-0002-0623-0347
authors.initials: M
authors.lastname: Jerkic
authors.affiliation: Molecular Structure and Function Program, The Hospital for Sick Children, Toronto, ON, Canada M5G 0A4 ; Department of Immunology, University of Toronto, Toronto, ON, Canada M5S 1A8.
authors.forename: Valentin
authors.initials: V
authors.lastname: Sotov
authors.affiliation: Program in Physiology and Experimental Medicine, The Hospital for Sick Children, Toronto, ON, Canada M5G 0A4 ; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada M5S 1A8.
authors.forename: David N
authors.initials: DN
authors.lastname: Douda
authors.affiliation: Molecular Structure and Function Program, The Hospital for Sick Children, Toronto, ON, Canada M5G 0A4 ; Department of Immunology, University of Toronto, Toronto, ON, Canada M5S 1A8 ; Division of Rheumatology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada M5G 1X8.
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Ardelean
authors.affiliation: Molecular Structure and Function Program, The Hospital for Sick Children, Toronto, ON, Canada M5G 0A4.
authors.forename: Niousha
authors.identifier: 0000-0003-0063-7629
authors.initials: N
authors.lastname: Ghamami
authors.affiliation: Department of Periodontology, Faculty of Dentistry, University of Toronto, Toronto, ON, Canada M5G 1G6.
authors.forename: Flavia
authors.identifier: 0000-0001-6693-1906
authors.initials: F
authors.lastname: Lakschevitz
authors.affiliation: Program in Physiology and Experimental Medicine, The Hospital for Sick Children, Toronto, ON, Canada M5G 0A4.
authors.forename: Meraj A
authors.initials: MA
authors.lastname: Khan
authors.affiliation: Department of Immunology, University of Toronto, Toronto, ON, Canada M5S 1A8.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Robertson
authors.affiliation: Department of Periodontology, Faculty of Dentistry, University of Toronto, Toronto, ON, Canada M5G 1G6.
authors.forename: Michael
authors.identifier: 0000-0002-6248-5977
authors.initials: M
authors.lastname: Glogauer
authors.affiliation: Department of Immunology, University of Toronto, Toronto, ON, Canada M5S 1A8.
authors.forename: Dana J
authors.initials: DJ
authors.lastname: Philpott
authors.affiliation: Program in Physiology and Experimental Medicine, The Hospital for Sick Children, Toronto, ON, Canada M5G 0A4 ; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada M5S 1A8 ; Institute of Medical Science, University of Toronto, Toronto, ON, Canada M5S 1A8.
authors.forename: Nades
authors.identifier: 0000-0002-2170-8548
authors.initials: N
authors.lastname: Palaniyar
authors.affiliation: Molecular Structure and Function Program, The Hospital for Sick Children, Toronto, ON, Canada M5G 0A4 ; Department of Immunology, University of Toronto, Toronto, ON, Canada M5S 1A8.
authors.forename: Michelle
authors.identifier: 0000-0002-5901-7582
authors.initials: M
authors.lastname: Letarte
mesh_terms: D000818:Animals; D054360:Chemokine CXCL1 / Q000378:metabolism; D003092:Colitis / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D000071063:Endoglin; D006579:Heterozygote; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D054360:Chemokine CXCL1; D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D053773:Transforming Growth Factor beta1
references.citation: Clin Infect Dis. 2007 Mar 15;44(6):841-5
references.pmid: 17304458
references.citation: Eur J Immunol. 1992 Feb;22(2):393-7
references.pmid: 1537377
references.citation: Blood. 2004 Dec 1;104(12):3758-65
references.pmid: 15308574
references.citation: Angiogenesis. 2014 Jul;17(3):641-59
references.pmid: 24510304
references.citation: Front Physiol. 2011 Nov 29;2:89
references.pmid: 22164144
references.citation: Circulation. 2005 Jun 7;111(22):2935-42
references.pmid: 15927970
references.citation: Oxid Med Cell Longev. 2012;2012:686972
references.pmid: 23320130
references.citation: J Immunol. 1995 May 1;154(9):4456-65
references.pmid: 7722302
references.citation: Am J Pathol. 2008 Jun;172(6):1457-66
references.pmid: 18458096
references.citation: Annu Rev Immunol. 2006;24:99-146
references.pmid: 16551245
references.citation: Am J Physiol. 1994 Aug;267(2 Pt 1):G316-21
references.pmid: 8074230
references.citation: Mediators Inflamm. 2011;2011:296069
references.pmid: 21765615
references.citation: Infect Immun. 2008 Mar;76(3):907-15
references.pmid: 18160481
references.citation: Thromb Haemost. 2007 May;97(5):755-62
references.pmid: 17479186
references.citation: Angiogenesis. 2014 Jan;17(1):129-46
references.pmid: 24061911
references.citation: Clin Neurol Neurosurg. 2012 Apr;114(3):235-40
references.pmid: 22093524
references.citation: Inflamm Bowel Dis. 2008 Oct;14(10):1443-52
references.pmid: 18421761
references.citation: Nat Rev Mol Cell Biol. 2007 Nov;8(11):857-69
references.pmid: 17895899
references.citation: J Immunol. 1988 Sep 15;141(6):1925-33
references.pmid: 3262644
references.citation: Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15813-8
references.pmid: 19805227
references.citation: Am J Respir Cell Mol Biol. 1994 Jul;11(1):95-102
references.pmid: 8018341
references.citation: Am J Physiol Gastrointest Liver Physiol. 2009 Oct;297(4):G768-80
references.pmid: 19643954
references.citation: J Leukoc Biol. 2005 May;77(5):598-625
references.pmid: 15689384
references.citation: J Cell Sci. 2013 Mar 15;126(Pt 6):1392-405
references.pmid: 23418351
references.citation: Mol Cell Biol. 2003 Aug;23(16):5664-79
references.pmid: 12897139
references.citation: J Clin Invest. 1997 Nov 15;100(10):2568-79
references.pmid: 9366572
references.citation: Circulation. 2006 Nov 21;114(21):2288-97
references.pmid: 17088457
references.citation: Blood. 2011 Nov 3;118(18):5040-9
references.pmid: 21900199
references.citation: J Clin Invest. 1999 Nov;104(10):1343-51
references.pmid: 10562296
references.citation: Circ Res. 2008 Oct 10;103(8):804-12
references.pmid: 18787191
references.citation: Nat Genet. 1994 Dec;8(4):345-51
references.pmid: 7894484
references.citation: J Biol Chem. 2011 Aug 26;286(34):30034-46
references.pmid: 21737454
references.citation: Annu Rev Immunol. 2005;23:197-223
references.pmid: 15771570
references.citation: Cell. 2010 Mar 19;140(6):871-82
references.pmid: 20303877
references.citation: Int J Cardiol. 2013 Sep 30;168(2):692-706
references.pmid: 23664438
references.citation: Angiogenesis. 2008;11(1):79-89
references.pmid: 18283546
references.citation: FASEB J. 2004 Mar;18(3):609-11
references.pmid: 14734648
references.citation: Circ Res. 2012 Jan 6;110(1):159-73
references.pmid: 22223212
references.citation: FEMS Microbiol Ecol. 2009 Jun;68(3):351-62
references.pmid: 19302550
references.citation: Nat Protoc. 2007;2(10):2307-11
references.pmid: 17947970
references.citation: Inflamm Bowel Dis. 2010 Nov;16(11):1859-70
references.pmid: 20848471
references.citation: Am J Physiol Gastrointest Liver Physiol. 2007 Jul;293(1):G5-G18
references.pmid: 17463183
references.citation: J Biomed Biotechnol. 2012;2012:718617
references.pmid: 22665990
references.citation: Gastroenterology. 2005 Feb;128(2):411-23
references.pmid: 15685552
references.citation: Endocrinology. 1994 Jun;134(6):2645-57
references.pmid: 8194490
references.citation: Blood. 2001 Dec 15;98(13):3635-42
references.pmid: 11739167
references.citation: Mol Cell Endocrinol. 2012 Aug 15;359(1-2):101-6
references.pmid: 22037168
references.citation: Immunol Res. 2012 Sep;53(1-3):168-81
references.pmid: 22407577
references.citation: Vitam Horm. 2011;85:255-97
references.pmid: 21353885
references.citation: Nature. 2011 Jun 15;474(7351):298-306
references.pmid: 21677746
references.citation: Am J Pathol. 2001 Jun;158(6):2011-20
references.pmid: 11395379
references.citation: Blood. 2012 May 24;119(21):5037-47
references.pmid: 22474252
references.citation: J Biol Chem. 1999 Jan 8;274(2):584-94
references.pmid: 9872992
references.citation: Lab Invest. 2013 Jul;93(7):768-78
references.pmid: 23732813
references.citation: PLoS One. 2012;7(6):e26284
references.pmid: 22719818