1. MLKL and FADD Are Critical for Suppressing Progressive Lymphoproliferative Disease and Activating the NLRP3 Inflammasome.
- Author
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Zhang X, Fan C, Zhang H, Zhao Q, Liu Y, Xu C, Xie Q, Wu X, Yu X, Zhang J, and Zhang H
- Subjects
- Animals, Fas-Associated Death Domain Protein genetics, Lymphoproliferative Disorders immunology, Mice, Mice, Inbred C57BL, Mice, Knockout, Protein Kinases genetics, Fas-Associated Death Domain Protein immunology, Inflammasomes immunology, Lymphoproliferative Disorders genetics, NLR Family, Pyrin Domain-Containing 3 Protein immunology, Protein Kinases immunology
- Abstract
MLKL, a key component downstream of RIPK3, is suggested to be a terminal executor of necroptosis. Genetic studies have revealed that Ripk3 ablation rescues embryonic lethality in Fadd- or Caspase-8-deficient mice. Given that RIPK3 has also been implicated in non-necroptotic pathways including apoptosis and inflammatory signaling, it remains unclear whether the lethality in Fadd(-/-) mice is indeed caused by necropotosis. Here, we show that genetic deletion of Mlkl rescues the developmental defect in Fadd-deficient mice and that Fadd(-/-)Mlkl(-/-) mice are viable and fertile. Mlkl(-/-)Fadd(-/-) mice display significantly accelerated lymphoproliferative disease characterized by lymphadenopathy and splenomegaly when compared to Ripk3(-/-)Fadd(-/-) mice. Mlkl(-/-)Fadd(-/-) bone-marrow-derived macrophages and dendritic cells have impaired NLRP3 inflammasome activation associated with defects in ASC speck formation and NF-κB-dependent NLRP3 transcription. Our findings reveal that MLKL and FADD play critical roles in preventing lymphoproliferative disease and activating the NLRP3 inflammasome., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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