Document Type
Article
Publication Date
9-20-2016
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.
Recommended Citation
Zhang, Xixi; Fan, Cunxian; Zhang, Haiwei; Zhao, Qun; Liu, Yongbo; Xu, Chengxian; Xie, Qun; Wu, Xiaoxia; Yu, Xianjun; Zhang, Jianke; and Zhang, Haibing, "MLKL and FADD Are Critical for Suppressing Progressive Lymphoproliferative Disease and Activating the NLRP3 Inflammasome." (2016). Department of Microbiology and Immunology Faculty Papers. Paper 83.
https://jdc.jefferson.edu/mifp/83
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
PubMed ID
27498868
Comments
This article has been peer reviewed. It is the author’s final published version in Cell Reports
Volume 16, Issue 12, September 2016, Pages 3247-3259.
The published version is available at DOI: 10.1016/j.celrep.2016.06.103. Copyright © Zhang et al.