MLKL and FADD Are Critical for Suppressing Progressive Lymphoproliferative Disease and Activating the NLRP3 Inflammasome

• DOI: 10.1016/j.celrep.2016.06.103
• Publication Date: 2016-08-05T11:56:21Z
• Authors: Xixi Zhang; Cunxian Fan; Haiwei Zhang; Qun Zhao; Yongbo Liu; Chengxian Xu; Qun Xie; Xiaoxia Wu; Xianjun Yu; Jianke Zhang; Haibing Zhang
• Keywords: FADD; RIPK1; Caspase 8

MLKL, a key component downstream of RIPK3, is suggested to be terminal executor necroptosis. Genetic studies have revealed that Ripk3 ablation rescues embryonic lethality in Fadd- or Caspase-8-deficient mice. Given RIPK3 has also been implicated non-necroptotic pathways including apoptosis and inflammatory signaling, it remains unclear whether the Fadd(-/-) mice indeed caused by necropotosis. Here, we show genetic deletion Mlkl developmental defect Fadd-deficient Fadd(-/-)Mlkl(-/-) are viable fertile. Mlkl(-/-)Fadd(-/-) display significantly accelerated lymphoproliferative disease characterized lymphadenopathy splenomegaly when compared Ripk3(-/-)Fadd(-/-) bone-marrow-derived macrophages dendritic cells impaired NLRP3 inflammasome activation associated with defects ASC speck formation NF-κB-dependent transcription. Our findings reveal MLKL FADD play critical roles preventing activating inflammasome.