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

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  • Sudan He
    Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital, Soochow University, Suzhou 215123, China; and
  • Yuqiong Liang
    National Institute of Biological Sciences, Beijing 102206, China
  • Feng Shao
    National Institute of Biological Sciences, Beijing 102206, China
  • Xiaodong Wang
    National Institute of Biological Sciences, Beijing 102206, China

Abstract

<jats:p>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, these data indicate that there are multiple upstream necrosis-initiating signaling pathways converging on the RIP3 during an innate immune response to viral and bacterial infections in mammals.</jats:p>

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