UNLABELLED: The current model for liver regeneration suggests that cell damage triggers Toll-like receptor (TLR) signaling via MyD88, leading to the induction of nuclear factor kappaB (NF-kappaB) and secretion of inflammatory cytokines that in turn prime liver regeneration. TLR3 is unique among TLRs in that it signals through TRIF (TIR domain-containing adaptor-inducing interferon-beta), not through MyD88, and may lead to activation of either the inflammatory or apoptotic pathway. The inflammatory pathway leads to NF-kappaB activation, whereas the apoptotic pathway, believed to be mediated by Rip3, leads to caspase-8 activation. In this study, we explored the role of TLR3 in liver regeneration by comparing the response to 70% partial hepatectomy of TLR3(wt) and TLR3(-/-) mice. We found that following partial hepatectomy, TLR3(-/-) mice demonstrated earlier hepatocyte proliferation. Furthermore, within the first hours, we observed a dramatic TLR3-dependent NF-kappaB activation and an increase in Rip3 levels in hepatocytes, accompanied by caspase-8 activation but without an apoptotic outcome. CONCLUSION: TLR3 plays an inhibitory role in the priming of liver regeneration, thus reinforcing the role of the innate immune system in balancing tissue regeneration.
UNLABELLED: The current model for liver regeneration suggests that cell damage triggers Toll-like receptor (TLR) signaling via MyD88, leading to the induction of nuclear factor kappaB (NF-kappaB) and secretion of inflammatory cytokines that in turn prime liver regeneration. TLR3 is unique among TLRs in that it signals through TRIF (TIR domain-containing adaptor-inducing interferon-beta), not through MyD88, and may lead to activation of either the inflammatory or apoptotic pathway. The inflammatory pathway leads to NF-kappaB activation, whereas the apoptotic pathway, believed to be mediated by Rip3, leads to caspase-8 activation. In this study, we explored the role of TLR3 in liver regeneration by comparing the response to 70% partial hepatectomy of TLR3(wt) and TLR3(-/-) mice. We found that following partial hepatectomy, TLR3(-/-) mice demonstrated earlier hepatocyte proliferation. Furthermore, within the first hours, we observed a dramatic TLR3-dependent NF-kappaB activation and an increase in Rip3 levels in hepatocytes, accompanied by caspase-8 activation but without an apoptotic outcome. CONCLUSION:TLR3 plays an inhibitory role in the priming of liver regeneration, thus reinforcing the role of the innate immune system in balancing tissue regeneration.
Authors: Sanjoy Roychowdhury; Dian J Chiang; Palash Mandal; Megan R McMullen; Xiuli Liu; Jessica I Cohen; John Pollard; Ariel E Feldstein; Laura E Nagy Journal: Alcohol Clin Exp Res Date: 2012-01-24 Impact factor: 3.455
Authors: Javier Vaquero; Jean S Campbell; Jamil Haque; Ryan S McMahan; Kimberly J Riehle; Renay L Bauer; Nelson Fausto Journal: Hepatology Date: 2011-06-26 Impact factor: 17.425
Authors: Kimberly J Riehle; Jamil Haque; Ryan S McMahan; Terrance J Kavanagh; Nelson Fausto; Jean S Campbell Journal: J Liver Disease Transplant Date: 2013-01-12