Toll-like receptor 3 signaling attenuates liver regeneration

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.

TLR3 plays an inhibitory role in the priming of liver regeneration, thus reinforcing the role of the innate immune system in balancing tissue regeneration.