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首页> 外文期刊>Cell Reports >MLKL and FADD Are Critical for Suppressing Progressive Lymphoproliferative Disease and Activating the NLRP3 Inflammasome
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MLKL and FADD Are Critical for Suppressing Progressive Lymphoproliferative Disease and Activating the NLRP3 Inflammasome

机译：MLKL和FADD对于抑制进行性淋巴细胞增生性疾病和激活NLRP3炎性体至关重要

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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-@kB-dependent NLRP3 transcription. Our findings reveal that MLKL and FADD play critical roles in preventing lymphoproliferative disease and activating the NLRP3 inflammasome.
机译：MLKL是RIPK3下游的关键组成部分，被认为是坏死病的最终执行者。遗传研究表明，Ripk3消融可挽救Fadd或Caspase-8缺陷小鼠的胚胎致死率。考虑到RIPK3也已经参与了包括细胞凋亡和炎性信号传导在内的非坏死性途径，因此尚不清楚Fadd ^-^ / ^-小鼠中的致死性是否确实是由坏死病引起的。在这里，我们显示了Mlk1的基因缺失挽救了Fadd缺陷型小鼠的发育缺陷，并且Fadd ^-^ / ^-Mlkl ^-^ / ^-小鼠是可行的和可育的。与Ripk3--//-Fadd--//-小鼠相比，Mlk1--//-Fadd--//-小鼠表现出明显加速的淋巴增生性疾病，其特征在于淋巴结肿大和脾肿大。 Mlk1 ^-^ / ^-Fadd ^-^ / ^-骨髓来源的巨噬细胞和树突细胞损害了与ASC斑点形成和NF- @ kB依赖的NLRP3转录缺陷有关的NLRP3炎性小体活化。我们的发现表明，MLKL和FADD在预防淋巴增生性疾病和激活NLRP3炎性体中起关键作用。

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