title: VEGF-C-dependent stimulation of lymphatic function ameliorates experimental inflammatory bowel disease.
abstract: Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBDs) of unknown etiology that are associated with an aberrant mucosal immune response. Neoangiogenesis and vascular injury are observed in IBD along with increased lymphangiogenesis. While the pathogenic role of angiogenesis in IBD is well characterized, it is not clear how or if increased lymphangiogenesis promotes disease. Here, we determined that enhancing lymphangiogenesis and lymphatic function reduces experimental IBD. Specifically, we demonstrated that adenoviral induction of prolymphangiogenic factor VEGF-C provides marked protection against the development of acute and chronic colitis in 2 different animal models. VEGF-C-dependent protection was observed in combination with increased inflammatory cell mobilization and bacterial antigen clearance from the inflamed colon to the draining lymph nodes. Moreover, we found that the VEGF-C/VEGFR3 pathway regulates macrophage (MΦ) plasticity and activation both in cultured MΦs and in vivo, imparting a hybrid M1-M2 phenotype. The protective function of VEGF-C was meditated by the so-called resolving MΦs during chronic experimental colitis in a STAT6-dependent manner. Together, these findings shed light on the contribution of lymphatics to the pathogenesis of gut inflammation and suggest that correction of defective lymphatic function with VEGF-C has potential as a therapeutic strategy for IBD.
authors.forename: Silvia
authors.initials: S
authors.lastname: D'Alessio
authors.forename: Carmen
authors.initials: C
authors.lastname: Correale
authors.forename: Carlotta
authors.initials: C
authors.lastname: Tacconi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gandelli
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pietrogrande
authors.forename: Stefania
authors.initials: S
authors.lastname: Vetrano
authors.forename: Marco
authors.initials: M
authors.lastname: Genua
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Arena
authors.forename: Antonino
authors.initials: A
authors.lastname: Spinelli
authors.forename: Laurent
authors.initials: L
authors.lastname: Peyrin-Biroulet
authors.forename: Claudio
authors.initials: C
authors.lastname: Fiocchi
authors.forename: Silvio
authors.initials: S
authors.lastname: Danese
mesh_terms: D000818:Animals; D003106:Colon / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000209:etiology* / Q000276:immunology; D042583:Lymphangiogenesis / Q000502:physiology*; D042601:Lymphatic Vessels / Q000502:physiology; D008262:Macrophage Activation; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D042582:Vascular Endothelial Growth Factor C / Q000502:physiology*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000502:physiology
chemical_list: D042582:Vascular Endothelial Growth Factor C; D040321:Vascular Endothelial Growth Factor Receptor-3
references.citation: Physiol Rev. 2002 Jul;82(3):673-700
references.pmid: 12087132
references.citation: World J Gastrointest Surg. 2012 Oct 27;4(10):228-33
references.pmid: 23443404
references.citation: Thromb Haemost. 2003 Aug;90(2):167-84
references.pmid: 12888864
references.citation: Annu Rev Immunol. 2009;27:451-83
references.pmid: 19105661
references.citation: Blood. 2007 Nov 1;110(9):3158-67
references.pmid: 17625067
references.citation: Gastroenterology. 2012 Jan;142(1):46-54.e42; quiz e30
references.pmid: 22001864
references.citation: Microvasc Res. 2006 Nov;72(3):161-71
references.pmid: 16876204
references.citation: Gastroenterology. 2006 Jun;130(7):2060-73
references.pmid: 16762629
references.citation: J Leukoc Biol. 2011 Sep;90(3):483-92
references.pmid: 21685246
references.citation: Science. 2002 Jun 7;296(5574):1883-6
references.pmid: 11976409
references.citation: Lab Invest. 1993 Aug;69(2):238-49
references.pmid: 8350599
references.citation: Blood. 2005 Jun 15;105(12):4642-8
references.pmid: 15746084
references.citation: Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9517-22
references.pmid: 22647600
references.citation: Gastroenterology. 2002 Jan;122(1):94-105
references.pmid: 11781285
references.citation: J Pathol. 2003 Jan;199(1):28-35
references.pmid: 12474223
references.citation: Dig Dis Sci. 2004 Apr;49(4):556-64
references.pmid: 15185857
references.citation: Am J Physiol Heart Circ Physiol. 2006 Sep;291(3):H1402-10
references.pmid: 16648194
references.citation: Inflamm Bowel Dis. 2013 Aug;19(9):1983-9
references.pmid: 23835443
references.citation: J Clin Invest. 2005 Feb;115(2):247-57
references.pmid: 15668734
references.citation: J Immunol. 1996 Oct 15;157(8):3220-2
references.pmid: 8871614
references.citation: Inflamm Bowel Dis. 2005 Oct;11(10):883-9
references.pmid: 16189417
references.citation: Gastroenterology. 2010 Apr;138(4):1395-405
references.pmid: 20044996
references.citation: Gut. 2007 Jun;56(6):855-62
references.pmid: 17170016
references.citation: Am J Clin Pathol. 1981 Oct;76(4):385-94
references.pmid: 6117198
references.citation: Blood. 2011 Dec 22;118(26):e192-208
references.pmid: 22012065
references.citation: Am J Pathol. 2002 Sep;161(3):947-56
references.pmid: 12213723
references.citation: Blood. 2009 May 28;113(22):5650-9
references.pmid: 19346498
references.citation: FASEB J. 2002 Dec;16(14):1985-7
references.pmid: 12397087
references.citation: Cancer Res. 2006 Aug 15;66(16):8065-75
references.pmid: 16912183
references.citation: Blood. 2013 Sep 26;122(13):2151-61
references.pmid: 23836558
references.citation: Virchows Arch. 2008 Jan;452(1):57-63
references.pmid: 18040712
references.citation: Nat Protoc. 2007;2(3):541-6
references.pmid: 17406617
references.citation: Am J Pathol. 2001 Sep;159(3):893-903
references.pmid: 11549582
references.citation: Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12677-82
references.pmid: 11592985
references.citation: Inflamm Bowel Dis. 2011 Aug;17(8):1814-21
references.pmid: 21744436
references.citation: Am J Pathol. 2005 Mar;166(3):913-21
references.pmid: 15743802
references.citation: Nat Med. 2007 Dec;13(12):1458-66
references.pmid: 18059280
references.citation: J Natl Cancer Inst. 2005 Jan 5;97(1):14-21
references.pmid: 15632376
references.citation: Cancer Res. 2002 Mar 1;62(5):1315-20
references.pmid: 11888898
references.citation: Nat Med. 2001 Feb;7(2):199-205
references.pmid: 11175851
references.citation: Aliment Pharmacol Ther. 2011 Sep;34(5):533-43
references.pmid: 21736598
references.citation: Proc R Soc Med. 1971 Feb;64(2):157-61
references.pmid: 5548937
references.citation: World J Surg. 1998 Apr;22(4):382-9
references.pmid: 9523521
references.citation: J Leukoc Biol. 2006 Oct;80(4):802-15
references.pmid: 16888083
references.citation: Am J Physiol Gastrointest Liver Physiol. 2011 May;300(5):G716-22
references.pmid: 21233277
references.citation: Am J Physiol Heart Circ Physiol. 2008 Mar;294(3):H1326-34
references.pmid: 18203849
references.citation: Virchows Arch. 2003 Mar;442(3):231-7
references.pmid: 12647212
references.citation: Am J Physiol Gastrointest Liver Physiol. 2013 May 1;304(9):G781-92
references.pmid: 23494123
references.citation: Immunity. 2010 May 28;32(5):593-604
references.pmid: 20510870
references.citation: APMIS. 2014 Nov;122(11):1125-9
references.pmid: 24730532
references.citation: J Immunol. 2006 Sep 1;177(5):3369-79
references.pmid: 16920978
references.citation: J Clin Invest. 1996 Aug 15;98(4):1010-20
references.pmid: 8770874
references.citation: Mol Cancer Ther. 2012 Aug;11(8):1637-49
references.pmid: 22584122
references.citation: Gut. 2008 Jan;57(1):1-4
references.pmid: 18094195
references.citation: Autoimmun Rev. 2004 Jul;3(5):394-400
references.pmid: 15288007
references.citation: Expert Rev Mol Med. 2009 May 14;11:e14
references.pmid: 19439108
references.citation: Genes Immun. 2001 Aug;2(5):287-9
references.pmid: 11528525
references.citation: Eur J Hum Genet. 2003 Nov;11(11):884-7
references.pmid: 14571275
references.citation: Cell. 1993 Oct 22;75(2):263-74
references.pmid: 8402911
references.citation: Inflamm Bowel Dis. 2010 Jun;16(6):1029-39
references.pmid: 19902545
references.citation: Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3566-70
references.pmid: 7724599
references.citation: Digestion. 1980;20(5):307-13
references.pmid: 7390055
references.citation: Science. 1997 May 30;276(5317):1423-5
references.pmid: 9162011
references.citation: J Clin Invest. 2007 Jul;117(7):1951-60
references.pmid: 17557119
references.citation: Clin Exp Immunol. 2003 Mar;131(3):446-50
references.pmid: 12605697
references.citation: PLoS One. 2012;7(7):e41797
references.pmid: 22848611
references.citation: World J Gastroenterol. 2006 Aug 14;12(30):4807-12
references.pmid: 16937461
references.citation: Am J Physiol Gastrointest Liver Physiol. 2006 Oct;291(4):G566-74
references.pmid: 16675748
references.citation: Trends Immunol. 2008 Nov;29(11):555-64
references.pmid: 18838297
references.citation: Am J Physiol Gastrointest Liver Physiol. 2007 Jul;293(1):G5-G18
references.pmid: 17463183
references.citation: Blood. 2011 Apr 28;117(17):4667-78
references.pmid: 21364190
references.citation: Clin Exp Immunol. 1999 Dec;118(3):337-9
references.pmid: 10594548
references.citation: Int J Exp Pathol. 2007 Apr;88(2):85-94
references.pmid: 17408451
references.citation: J Clin Invest. 2003 Mar;111(5):717-25
references.pmid: 12618526
references.citation: N Engl J Med. 2002 Aug 8;347(6):417-29
references.pmid: 12167685
references.citation: Immunity. 2006 Feb;24(2):203-15
references.pmid: 16473832
references.citation: Dig Dis Sci. 2003 Feb;48(2):408-14
references.pmid: 12643623
references.citation: Curr Opin Immunol. 2009 Oct;21(5):506-13
references.pmid: 19665880
references.citation: Blood. 2008 Nov 15;112(10):4117-27
references.pmid: 18779392
references.citation: World J Gastroenterol. 2008 Jan 21;14(3):390-400
references.pmid: 18200661
references.citation: Inflamm Bowel Dis. 2013 Sep;19(10):2084-90
references.pmid: 23851640