Deficient chaperone-mediated autophagy facilitates LPS-induced microglial activation via regulation of the p300/NF-κB/NLRP3 pathway

Neuroinflammation is a pathological change that is involved in the progression of Parkinson's disease. Dysfunction of chaperone-mediated autophagy (CMA) has proinflammatory effects. However, the mechanism by which CMA mediates inflammation and whether CMA affects microglia and microglia-mediated neuronal damage remain to be elucidated. In the present study, we found that LAMP2A, a limiting protein for CMA, was decreased in lipopolysaccharide (LPS)-treated primary microglia. Activation of CMA by the activator CA significantly repressed LPS-induced microglial activation, whereas CMA dysfunction exacerbated microglial activation. We further identified that the protein p300 was a substrate of CMA. Degradation of p300 by CMA reduced p65 acetylation, thereby inhibiting the transcription of proinflammatory factors and the activation of the NLRP3 inflammasome. Furthermore, CA pretreatment inhibited microglia-mediated inflammation and, in turn, attenuated neuronal death in vitro and in vivo. Our findings suggest repressive effects of CMA on microglial activation through the p300-associated NF-kappa B signaling pathway, thus uncovering a mechanistic link between CMA and neuroinflammation.

Automated summary

This study investigates the role of chaperone-mediated autophagy (CMA) in neuroinflammation and its impact on microglia activation and neuronal damage. The researchers found that CMA activation can inhibit microglial activation and inflammation through the p300-associated NF-kappa B signaling pathway. Additionally, they demonstrated that CMA dysfunction worsens microglial activation and inflammation. These findings provide insight into the mechanistic link between CMA and neuroinflammation.