| The NLRP3 inflammasome known as a multiprotein complexes has been involved in a wild range of diseases including obesity, Gout, Alzheimer’s diseases and autoinflammatory. Pathogen-associated molecular patterns(PAMPs) and damage-associated molecular patterns(DAMPs) have been reported to activate the NLRP3 inflammasome. Upon activation, the NLRP3 inflammasome serves as a platform for activation of the cysteine protease Caspase-1, which leads to the secretion of the proinflammatory cytokines IL-1b and IL-18. The NLRP3 inflammasome pathway belongs to immune surveillance mechanism and can help tissue repair. However, one concern that should be taken into account is dysregulated NLRP3 inflammasome activation is associated with many inflammatory diseases. Three common events that are required for the activationof NLRP3 inflammasome are a potassium efflux, lysosomal protease leakage and the generation of Reactive Oxygen Species(ROS). Mitochondria which are the main resource of ROS has been proven to relate to NLRP3 inflammasome activation. Previous studies demonstrates that the NLRP3 inflammasome is negatively regulated by mitophagy which removes the damaged mitochondria and accumulated ROS. Here we report that Jnk2 deficiency in MEFs induced excessive autophagic activity, resulting in lysosomal degradation of the mitophagy adaptor p62 in the steady state. The depletion of p62 prevented Jnk2-deficient cells from mounting mitophagy upon stress and caused the accumulation of dysfunctional mitochondria and ROS. Loss of Jnk2 enhanced the NLRP3 inflammasome-dependent IL18 and IL-1b secretion and increased mortality in LPS-induced septic shock mice model. Taken together, our studies show that Jnk2 prevents the hyperactivation of the NLRP3 inflammasome through the improvement of mitochondrial quality control and the removal of ROS. This control mechanism may provide insight into the potential therapeutic targets for mitigating inflammatory diseases. |
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