Negative regulation of autophagy in activating nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 inﬂammasomes in the hippocampus of an epilepsy rat model
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AbstractEpilepsy, characterized by unpredictable and periodic seizures, is associated with chronic hippocampal inﬂammation and autophagy. Moreover, a molecular relationship between autophagy and inﬂammation in neurodegenerative disorders has been reported, highlighting the role of autophagy in the regulation of inﬂammation. To the best of our knowledge, there is no previous evidence of an association between nucleotide-binding oligomerization domain-like receptor family pyrin domaincontaining 3 (NLRP3) inﬂammasome and autophagy in epilepsy. Hence, we in this study aimed at investigating the possible association between NLRP3 inﬂammasome activation and autophagy in the development of epilepsy. A rat model of temporal lobe epilepsy was induced with lithiumpilocarpine. Five groups, i.e., control (n=20), status epilepticus (SE, n=30), SE+control (siRNA; n=15), SE+NLRP3 siRNA (n=30), and SE+wortmannin (n=30), were investigated. Real-time quantitative reverse transcription polymerase chain reaction, Western blotting, and quantum dotbased immunohistochemistry were used to detect the mRNA/protein expression levels of NLRP3, caspase-1, interleukin (IL)-1, IL-18, Beclin-1, and microtubule-associated protein light chain 3 (LC3) in the hippocampus. In addition, transmission electron microscopy was utilized to investigate autophagosome in the hippocampus of SE rats. We found that mRNA and protein expressions of NLRP3, caspase-1, IL-1, IL-18, LC3, and Beclin-1 were activated in the hippocampus. Gene silencing of NLRP3 suppressed caspase-1, IL-1, and IL-18 release and signiﬁcantly ameliorated hippocampal damage. Furthermore, the LC3 and Beclin-1 expression levels decreased signiﬁcantly after treatment with wortmannin. Importantly, NLRP3 inﬂammasome activation and IL-1/IL-18 releases were signiﬁcantly enhanced after treatment with wortmannin, which implied a negative association between autophagy inhibition and NLRP3 inﬂammasome activation. Our study provides the ﬁrst evidence that autophagy plays an important role in NLRP3 inﬂammasome activation in the development of epilepsy. These ﬁndings suggest that regulation of autophagy may be a promising potential strategy for treating patients with epilepsy.
CitationWu J, Chen L, Wang S, Li Y, Liu L, Chen G, Wang S, Zhou S (2019) 'Negative regulation of autophagy in activating nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 inﬂammasomes in the hippocampus of an epilepsy rat model', Nanoscience and Nanotechnology Letters, 11 (7), pp.947-959.
PublisherAmerican Scientific Publishers