title: Nucleotide-binding oligomerization domain 2 signaling promotes hyperresponsive macrophages and colitis in IL-10-deficient mice.
abstract: IL-10 contributes to the maintenance of intestinal homeostasis via the regulation of inflammatory responses to enteric bacteria. Loss of IL-10 signaling results in spontaneous colitis in mice and early onset enterocolitis in humans. Nucleotide-binding oligomerization domain (NOD) 2 is an intracellular receptor of bacterial peptidoglycan products, and, although NOD2 mutations are associated with Crohn's disease, the precise role of NOD2 in the development of intestinal inflammation remains undefined. To determine the role of NOD2 in the development of colitis on the clinically relevant genetic background of IL-10-deficient signaling, we generated mice lacking IL-10 and NOD2 (IL-10(-/-)NOD2(-/-)). Loss of NOD2 in IL-10(-/-) mice resulted in significant amelioration of chronic colitis, indicating that NOD2 signaling promotes the development of intestinal inflammation in IL-10(-/-) mice. Contrary to previous reports investigating immune function in NOD2(-/-) mice, T cell proliferative capacity and IL-2 production were not impaired, and immune polarization toward type 1 immunity was not affected. However, loss of NOD2 in IL-10-deficient macrophages reduced IL-6, TNF-α, and IL-12p40 production in response to bacterial stimulation. Further analysis of the intrinsic macrophage response before the onset of inflammation revealed that, in the absence of IL-10, synergistic signaling between various TLRs and NOD2 resulted in hyperresponsive, proinflammatory macrophages, thus providing the appropriate immune environment for the development of colitis. Data presented in this study demonstrate that NOD2 signaling contributes to intestinal inflammation that arises through loss of IL-10 and provides mechanistic insight into the development of colitis in inflammatory bowel disease patients with impaired IL-10 signaling.
authors: Cardiovascular and Metabolic Diseases, Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors: Joanna
authors: J
authors: Jamontt
authors: Stephanie
authors: S
authors: Petit
authors: Natalie
authors: N
authors: Clark
authors: Scott J
authors: SJ
authors: Parkinson
authors: Philip
authors: P
authors: Smith
mesh_terms: D000818:Animals; D002908:Chronic Disease; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018836:Inflammation Mediators / Q000502:physiology; D016753:Interleukin-10 / Q000172:deficiency* / Q000235:genetics; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053473:Nod2 Signaling Adaptor Protein / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000276:immunology / Q000473:pathology; D051193:Toll-Like Receptors / Q000378:metabolism / Q000502:physiology
chemical_list: C556062:IL10 protein, mouse; D018836:Inflammation Mediators; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D051193:Toll-Like Receptors; D016753:Interleukin-10
references: Nature. 2001 May 31;411(6837):603-6
references: 11385577
references: J Leukoc Biol. 2006 Apr;79(4):860-6
references: 16461743
references: Nature. 2001 May 31;411(6837):599-603
references: 11385576
references: Nat Immunol. 2009 Dec;10(12):1267-74
references: 19881508
references: Cell. 2004 Jul 23;118(2):229-41
references: 15260992
references: J Immunol. 2003 Apr 15;170(8):3939-43
references: 12682220
references: PLoS One. 2008 Jul 23;3(7):e2769
references: 18648508
references: Immunity. 2006 Aug;25(2):319-29
references: 16879997
references: Nat Immunol. 2009 May;10(5):471-9
references: 19349988
references: J Biol Chem. 2002 Oct 18;277(42):39179-86
references: 12151399
references: Gastroenterology. 2002 Jan;122(1):94-105
references: 11781285
references: Infect Immun. 2005 Dec;73(12):7967-76
references: 16299289
references: J Immunol. 2008 Dec 1;181(11):7925-35
references: 19017983
references: Curr Opin Pharmacol. 2006 Aug;6(4):379-86
references: 16713356
references: Cell Microbiol. 2005 Jan;7(1):53-61
references: 15617523
references: Inflamm Bowel Dis. 2009 Nov;15(11):1686-96
references: 19572373
references: J Immunol. 2004 Jul 15;173(2):1240-8
references: 15240716
references: Gut. 2004 Nov;53(11):1658-64
references: 15479689
references: J Exp Med. 1994 Feb 1;179(2):589-600
references: 7905019
references: J Clin Invest. 2006 May;116(5):1310-6
references: 16670770
references: Cell Immunol. 2011;268(2):97-104
references: 21440248
references: J Clin Invest. 2003 May;111(9):1297-308
references: 12727921
references: J Immunol. 2010 Mar 1;184(5):2627-37
references: 20130211
references: Annu Rev Pathol. 2009;4:365-98
references: 18928408
references: J Clin Invest. 2008 Feb;118(2):545-59
references: 18188453
references: PLoS One. 2012;7(1):e30273
references: 22272321
references: J Immunol. 2005 May 15;174(10):6518-23
references: 15879155
references: Immunology. 2008 Apr;123(4):600-5
references: 18028374
references: J Exp Med. 1998 Feb 16;187(4):571-8
references: 9463407
references: J Immunol. 2011 Sep 15;187(6):2849-52
references: 21849681
references: Cell Microbiol. 2008 Oct;10(10):2067-77
references: 18549453
references: Gut. 2011 Aug;60(8):1050-9
references: 21471573
references: Eur J Immunol. 2005 Aug;35(8):2459-70
references: 16021602
references: Lancet. 2005 May 21-27;365(9473):1794-6
references: 15910952
references: Infect Immun. 2001 Apr;69(4):2045-53
references: 11254557
references: Gastroenterology. 2011 Jan;140(1):231-41
references: 20854823
references: Gastroenterology. 2009 Feb;136(2):523-9.e3
references: 19068216
references: Immunity. 1999 Jan;10(1):39-49
references: 10023769
references: Annu Rev Immunol. 2003;21:305-34
references: 12471050
references: N Engl J Med. 2009 Nov 19;361(21):2033-45
references: 19890111
references: J Exp Med. 1996 Jul 1;184(1):241-51
references: 8691138
references: Eur J Immunol. 2011 Jan;41(1):182-94
references: 21182089
references: Inflamm Res. 2002 Aug;51(8):409-15
references: 12234058
references: Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19440-5
references: 18032608
references: Eur J Immunol. 2008 Jan;38(1):184-91
references: 18157816
references: Immunity. 2009 May;30(5):616-25
references: 19464984
references: Annu Rev Immunol. 2010;28:573-621
references: 20192811
references: Science. 2005 Feb 4;307(5710):734-8
references: 15692052
references: Cell. 1993 Oct 22;75(2):263-74
references: 8402911
references: Eur J Immunol. 2004 Jul;34(7):2052-9
references: 15214053
references: J Biol Chem. 2003 Mar 14;278(11):8869-72
references: 12527755
references: J Immunol. 2003 Jul 15;171(2):971-8
references: 12847269
references: Gastroenterology. 2007 Apr;132(4):1359-74
references: 17408640
references: Mol Immunol. 2009 Feb;46(4):613-21
references: 18962896
references: Gastroenterology. 2004 Feb;126(2):520-8
references: 14762789
references: Gastroenterology. 1995 May;108(5):1434-44
references: 7729636
references: Dig Dis Sci. 2003 Feb;48(2):408-14
references: 12643623
references: Nat Genet. 2010 Dec;42(12):1118-25
references: 21102463
references: Nat Immunol. 2004 Aug;5(8):800-8
references: 15220916
references: Gastroenterology. 2009 Oct;137(4):1380-90.e1-3
references: 19596011
references: J Biol Chem. 2001 Feb 16;276(7):4812-8
references: 11087742
references: Gut. 2005 Nov;54(11):1553-7
references: 15928043
references: Science. 2005 Feb 4;307(5710):731-4
references: 15692051
references: Neth J Med. 2005 Sep;63(8):305-8
references: 16186640
references: J Leukoc Biol. 2009 May;85(5):896-903
references: 19237638
references: J Biol Chem. 2003 Feb 21;278(8):5509-12
references: 12514169
references: J Immunol. 2007 Feb 15;178(4):2380-6
references: 17277144
references: Nat Genet. 2008 Nov;40(11):1319-23
references: 18836448
references: J Proteome Res. 2009 Oct;8(10):4406-17
references: 19681597
references: PLoS One. 2007 Jun 13;2(6):e523
references: 17565376
references: J Immunol. 1991 May 15;146(10):3444-51
references: 1827484
references: Gastroenterology. 2011 Aug;141(2):653-62, 662.e1-4
references: 21679711
references: Mol Cell Biol. 2007 Sep;27(17):6012-25
references: 17562858