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Scientists discover the role of programmed cell death related proteins in suppressing lymphoaccumulative disease and activating NLRP3 inflammasome

Programmed cell death (PCD) is essential for the development, homeostasis, and pathological processes of mammals. Apoptosis and necroptosis are two different forms of PCD and can be regulated by distinct signaling pathways. Upon stimulation, death receptors recruit the adaptor protein FADD, which binds and activates caspase-8 to initiate apoptosis. When the activity of caspase-8 is inhibited, RIPK1 and RIPK3 interact mutually and form the necrosome which recruits and activates MLKL to execute necroptosis. As critical mediators of apoptosis and necroptosis, FADD and MLKL are believed to be involved in many physiological and pathological processes.

A research group led by Dr. Zhang Haibing from the Institute for Nutritional Sciences, SIBS, Chinese Academy of Sciences found that genetic deletion of Mlkl rescued the developmental defect in Fadd-deficient mice and the Mlkl and Fadd double knockout (DKO) mice were able to grow into fertile adults. However, these mice displayed significantly accelerated lymphoaccumulative disease when compared to the previously reported RIPK3 and FADD DKO mice. The disease started around 9-week-old and was characterized by systematic lymphadenopathy and splenomegaly and cells accumulated in spleen and lymph nodes were proved to be an abnormal population of CD3+B220+ T lymphocytes. Besides, the DKO mice had insensitive innate immune responses. The results showed that bone marrow derived macrophages and dendritic cells from these mice had impaired NLRP3 inflammasome activation when challenged with LPS or Poly(I:C). Further investigation revealed that the defects in DKO cells were due to weakened NF-kB dependent NLRP3 transcription which subsequently reduced the ASC speck formation and caspase-1 cleavage. Consistent with these results, researchers observed a potent reduction of cytokine release in DKO mice after LPS exposure. These findings reveal critical roles of PCD related protein FADD and MLKL in embryonic development, lymphoaccumulative disease and inflammatory responses. More importantly, it suggests that the key components of PCD pathways are multifunctional in regulating cell death and innate immune response, which may provide new approaches to therapies of cancer and immune disorders.

This work was published online in Cell Reports on August 4, 2016, as a research article entitled “MLKL and FADD are Critical for Suppressing Progressive Lymphoaccumulative Disease and Activating NLRP3 Inflammasome”. This study was funded by the National Natural Science Foundation of China and Thousand Young Talents Program of the Chinese government.

Author Contact:
Zhang Haibing, Ph.D., Principal Investigator
Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Tel: +86-21-54920988;
Fax: +86-21-54920988;
Email:hbzhang@sibs.ac.cn


MLKL and FADD are multifunctional in regulating cell death and innate immune response
Image by Dr. Zhang’s lab

Article website: http://www.sciencedirect.com/science/article/pii/S2211124716309251

 
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