Toll-like Receptor 3-mediated Necrosis via TRIF, RIP3, and MLKL

Toll-like receptor (TLR) signaling is triggered by pathogen-associated molecular patterns that mediate well established cytokine-driven pathways, activating NF-κB together with IRF3/IRF7. In addition, TLR3 drives caspase 8-regulated programmed cell death pathways reminiscent of TNF family death receptor signaling. We find that inhibition or elimination of caspase 8 during stimulation of TLR2, TLR3, TLR4, TLR5, or TLR9 results in receptor interacting protein (RIP) 3 kinase-dependent programmed necrosis that occurs through either TIR domain-containing adapter-inducing interferon-β (TRIF) or MyD88 signal transduction. TLR3 or TLR4 directly activates programmed necrosis through a RIP homotypic interaction…

• G
  GlaxoSmithKline
• CP
  Cancer Prevention and Research Institute of Texas
• UO
  University of Texas at Austin
• AC
  Atlanta Clinical and Translational Science Institute

  Award: UL1 RR025008
• NI
  National Institutes of Health

  Awards: RO1 AI030363, RR025008, UL1 RR025008, OD012198, AI020211