Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3–mediated pathway

We report here that mouse macrophages undergo receptor-interacting kinase-3 (RIP3)-dependent but TNF-α-independent necrosis when Toll-like receptors (TLR) 3 and 4 are activated by poly(I:C) and LPS, respectively. An adaptor protein, Toll/IL-1 receptor domain-containing adapter inducing IFN-β (TRIF/TICAM-1), which is dispensable for TNF-α-induced necrosis, forms a complex with RIP3 upon TLR3/TLR4 activation and is essential for TLR3/TLR4-induced necrosis. Mice without RIP3 or functional TRIF did not show macrophage loss and elevation of inflammatory cytokines when they were exposed to LPS. Necrosis in mouse macrophages induced by either TNFR or TLR3/TLR4 is executed by reactive oxygen species. Taken together,…

• NN
  National Natural Science Foundation of China
• MO
  Ministry of Science and Technology of the People's Republic of China
• GO
  Government of Jiangsu Province
• NS
  Natural Science Foundation of Jiangsu Province
• PA
  Priority Academic Program Development of Jiangsu Higher Education Institutions
• DF
  Directorate for Biological Sciences