Complement regulates TLR4-mediated inflammatory responses during intestinal ischemia reperfusion.
Innate immune responses including TLR4 and complement activation are required for mesenteric ischemia/reperfusion (IR)-induced tissue damage. We examined the regulation of TLR4 and complement activation in a mouse model of intestinal IR. Intestinal IR-induced C3 deposition in a TLR4 dependent manner. In addition, in wild-type but not TLR4 deficient mice, IR significantly increased C3 and Factor B (FB) mRNA expression within the intestine. To further examine the role of TLR4 and complement, we administered the complement inhibitor, CR2-Crry, to target local complement activation in wild-type C57Bl/10, and TLR4 deficient B10/ScN mice. TLR4 deficient mice sustained less damage and inflammation after IR than wild-type mice, but administration of CR2-Crry did not further reduce tissue damage. In contrast, CR2-Crry treatment of wild-type mice was accompanied by a reduction in complement activation and in C3 and FB transcription in response to IR. CR2-Crry also significantly decreased intestinal IL-6 and IL-12p40 production in both the wild-type and TLR4 deficient mice. These data indicate that TLR4 regulates extrahepatic complement production while complement regulates TLR4-mediated cytokine production during intestinal IR.
Pope
Michael R
MR
Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
Hoffman
Sara M
SM
Tomlinson
Stephen
S
Fleming
Sherry D
SD
D000818:Animals; D003167:Complement Activation / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000276:immunology* / Q000293:injuries; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D015427:Reperfusion Injury / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051197:Toll-Like Receptor 4 / Q000276:immunology* / Q000378:metabolism
C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4
Immunol Lett. 2003 Jan 22;85(2):85-95
12527213
Hepatology. 2009 Apr;49(4):1326-34
19133650
Mol Immunol. 1999 Sep-Oct;36(13-14):941-8
10698348
Mol Immunol. 2007 Jan;44(1-3):103-10
16876247
Surgery. 1999 Aug;126(2):343-8
10455904
J Immunol. 2001 Nov 15;167(10):5921-7
11698469
Surgery. 2007 May;141(5):563-9
17462455
Am J Reprod Immunol. 2008 Aug;60(2):135-40
18705840
Gastroenterology. 2006 Sep;131(3):862-77
16952555
FEMS Immunol Med Microbiol. 1999 Mar;23(3):259-69
10219599
J Appl Physiol (1985). 1999 Mar;86(3):938-42
10066708
J Clin Invest. 2005 Sep;115(9):2444-53
16127466
J Immunol. 2002 Aug 15;169(4):2126-33
12165541
Am J Physiol. 1998 Nov;275(5):R1584-92
9791077
Trends Immunol. 2007 Jan;28(1):33-8
17126601
Cancer Immunol Immunother. 2007 May;56(5):649-58
16947020
Clin Exp Immunol. 2000 Apr;120(1):30-7
10759760
Crit Rev Immunol. 2002;22(4):251-68
12678427
J Immunol. 2008 Jul 15;181(2):878-90
18606639
Blood. 2007 Jul 1;110(1):228-36
17363730
J Endotoxin Res. 2001;7(3):227-31
11581575
Matrix Biol. 2008 Mar;27(2):107-18
18023983
Curr Opin Crit Care. 2001 Apr;7(2):92-8
11373517
J Immunol. 1998 May 1;160(9):4553-60
9574562
J Leukoc Biol. 2004 Sep;76(3):514-9
15178705
Clin Exp Immunol. 1998 Mar;111(3):477-83
9528886
Blood. 2001 Jun 1;97(11):3466-9
11369638
J Leukoc Biol. 2009 Oct;86(4):971-80
19564573
Shock. 2009 Jul;32(1):4-16
19008778
Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15861-6
19717455
Gastroenterology. 2008 Jul;135(1):217-225.e1
18471439
Arch Surg. 1970 Oct;101(4):478-83
5457245
Nat Immunol. 2000 Sep;1(3):221-6
10973279
Immunity. 2005 Apr;22(4):415-26
15845447
Clin Immunol. 1999 Feb;90(2):266-75
10080839
Clin Immunol. 2003 Sep;108(3):263-73
14499250
Blood. 2009 Jul 30;114(5):1005-15
19491392
Pharmacol Rev. 1998 Mar;50(1):59-87
9549758
Gastroenterology. 2007 Dec;133(6):1869-81
18054559
Nat Rev Immunol. 2005 Jul;5(7):521-31
15999093
Am J Physiol Gastrointest Liver Physiol. 2005 May;288(5):G1055-65
15826931
Shock. 2007 Oct;28(4):384-93
17577136
Shock. 2006 Nov;26(5):430-7
17047512
Mol Immunol. 2006 Jan;43(1-2):13-21
16019071