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论文题目: MLKL and FADD Are Critical for Suppressing Progressive Lymphoproliferative Disease and Activating the NLRP3 Inflammasome
英文论文题目: MLKL and FADD Are Critical for Suppressing Progressive Lymphoproliferative Disease and Activating the NLRP3 Inflammasome
第一作者: Zhang, XX; Fan, CX; Zhang, HW; Zhao, Q; Liu, YB; Xu, CX; Xie, Q; Wu, XX; Yu, XJ; Zhang, JK; Zhang, HB
英文第一作者: Zhang, XX; Fan, CX; Zhang, HW; Zhao, Q; Liu, YB; Xu, CX; Xie, Q; Wu, XX; Yu, XJ; Zhang, JK; Zhang, HB
联系作者: Zhang, HB (reprint author), Chinese Acad Sci, Univ Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci,Key Lab Nutr & Metab, Shanghai 200031, Peoples R China.
英文联系作者: Zhang, HB (reprint author), Chinese Acad Sci, Univ Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci,Key Lab Nutr & Metab, Shanghai 200031, Peoples R China.
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发表年度: 2016
卷: 16
期: 12
页码: 3247-3259
摘要: 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-kappa B-dependent NLRP3 transcription. Our findings reveal that MLKL and FADD play critical roles in preventing lymphoproliferative disease and activating the NLRP3 inflammasome.
英文摘要: 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-kappa B-dependent NLRP3 transcription. Our findings reveal that MLKL and FADD play critical roles in preventing lymphoproliferative disease and activating the NLRP3 inflammasome.
刊物名称: CELL REPORTS
英文刊物名称: CELL REPORTS
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学科: Cell Biology
英文学科: Cell Biology
影响因子: 8.282
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论文类别: Article
英文论文类别: Article
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