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 C57BI/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 (C) 2010 Elsevier Ltd All rights reserved