Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 50, Pages 20054-20059Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1116302108
Keywords
necroptosis; bone marrow-derived macrophage
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Funding
- Chinese Ministry of Science and Technology [2008AA022318]
- Priority Academic Program Development of Jiangsu Higher Education Institutions PAPD
- National Natural Science Foundation of China [31171330]
- Natural Science Foundation of Jiangsu Province [BK2011287]
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We report here that mouse macrophages undergo receptor-interacting kinase-3 (RIP3)-dependent but TNF-alpha-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-beta (TRIF/TICAM-1), which is dispensable for TNF-alpha-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.
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