MLKL and FADD Are Critical for Suppressing Progressive Lymphoproliferative Disease and Activating the NLRP3 Inflammasome.
MLKL and FADD Are Critical for Suppressing Progressive Lymphoproliferative Disease and Activating the NLRP3 Inflammasome.
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MLKL 和 FADD 对于抑制进行性淋巴细胞增殖性疾病和激活 NLRP3 炎性体至关重要
DOI：
10.1016/j.celrep.2016.06.103
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发表时间：
2016-09-20
期刊：
影响因子：
8.8
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Zhang X;Fan C;Zhang H;Zhao Q;Liu Y;Xu C;Xie Q;Wu X;Yu X;Zhang J;Zhang H
MLKL是RIPK 3下游的一个关键组分，被认为是坏死性凋亡的终末执行者。遗传研究表明，Ripk 3消融挽救了Fadd或Caspase-8缺陷小鼠的胚胎致死率。鉴于RIPK 3也参与了非坏死性途径，包括细胞凋亡和炎症信号传导，目前尚不清楚Fadd−/−小鼠的致死性是否确实是由坏死性引起的。在这里，我们表明Mlkl的基因缺失可以挽救Fadd缺陷小鼠的发育缺陷，并且Fadd-/-Mlkl-/-小鼠可以存活且具有生育能力。与Ripk 3 −/− Fadd −/−小鼠相比，Mlkl−/−Fadd −/−小鼠表现出显著加速的淋巴组织增生性疾病，其特征为淋巴结病和脾肿大。Mlkl−/−Fadd−/−骨髓源性巨噬细胞和树突状细胞具有受损的NLRP 3炎性体活化，其与ASC斑点形成和NF-κ B依赖性NLRP 3转录缺陷相关。我们的研究结果表明，MLKL和FADD在预防淋巴组织增生性疾病和激活NLRP 3炎性体中起关键作用。Zhang等人发现RIPK 3-MLKL介导的信号传导导致Fadd缺陷小鼠的胚胎死亡。Mlkl−/−Fadd−/−小鼠比Fadd−/− Ripk 3 −/−小鼠具有更严重的淋巴组织增生性疾病。进一步的研究表明，MLKL和FADD通过调节ASC斑点形成和NF-κ B依赖的NLRP 3转录，对激活NLRP 3炎性体至关重要。
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-κB-dependent NLRP3 transcription. Our findings reveal that MLKL and FADD play critical roles in preventing lymphoproliferative disease and activating the NLRP3 inflammasome. Zhang et al. find that RIPK3-MLKL-mediated signaling results in embryonic lethality in Fadd-deficient mice. Mlkl−/−Fadd−/− mice have more severe lymphoproliferative disease than Fadd−/−Ripk3−/− mice. Further studies reveal that MLKL and FADD are critical for activating the NLRP3 inflammasome through regulation of ASC speck formation and NF-κB-dependent NLRP3 transcription.
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影响因子：
29.7
作者：
Davis BK;Wen H;Ting JP
通讯作者：
Ting JP
caspase-8脚手架函数和MLKL调节TLR3下游的NLRP3炎性体激活。
影响因子：
16.6
作者：
Kang, Seokwon;Fernandes-Alnemri, Teresa;Rogers, Corey;Mayes, Lindsey;Wang, Ying;Dillon, Christopher;Roback, Linda;Kaiser, William;Oberst, Andrew;Sagara, Junji;Fitzgerald, Katherine A.;Green, Douglas R.;Zhang, Jianke;Mocarski, Edward S.;Alnemri, Emad S.
通讯作者：
Alnemri, Emad S.
影响因子：
64.8
作者：
Oberst, Andrew;Dillon, Christopher P.;Weinlich, Ricardo;McCormick, Laura L.;Fitzgerald, Patrick;Pop, Cristina;Hakem, Razq;Salvesen, Guy S.;Green, Douglas R.
通讯作者：
Green, Douglas R.
影响因子：
5.5
作者：
Dowling JP;Nair A;Zhang J
通讯作者：
Zhang J
影响因子：
32.4
作者：
Kang, Tae-Bong;Yang, Seung-Hoon;Wallach, David
通讯作者：
Wallach, David