The NALP3 inflammasome is involved in neurotoxic prion peptide-induced microglial activation.
The NALP3 inflammasome is involved in neurotoxic prion peptide-induced microglial activation.
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NALP3炎症小体参与神经毒性朊病毒肽诱导的小胶质细胞激活
DOI：
10.1186/1742-2094-9-73
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发表时间：
2012-07-11
影响因子：
9.3
通讯作者：
Zhao D
中科院分区：
文献类型：
--
作者：
Shi F;Yang L;Kouadir M;Yang Y;Wang J;Zhou X;Yin X;Zhao D
研究背景朊病毒病（Prion diseases）是一种神经退行性疾病，其特征是与疾病相关的朊病毒蛋白PrPSc异常积聚。在朊病毒感染的大脑中，激活的小胶质细胞通常存在于PrPSc聚集体附近，并且小胶质细胞激活被认为在朊病毒疾病的发病机制中起关键作用。虽然朊病毒诱导的小胶质细胞释放白细胞介素（IL）-1β已被广泛报道，但朊病毒疾病中引发的小胶质细胞被激活并分泌IL-1β的机制尚未阐明。在这项研究中，我们研究了NACHT，LRR和PYD结构域蛋白（NALP）3炎性体在脂多糖（LPS）致敏的小胶质细胞暴露于合成的神经毒性朊病毒片段（PrP 106 -126）后释放IL-1β中的作用。使用ELISA评估IL-1β产生。通过定量PCR测量NALP 3、ASC和促炎因子的mRNA表达。结果PrP 106 - 126诱导的小胶质细胞释放IL-1β依赖于NALP 3炎性小体的激活，而炎性小体的激活是PrP 106 - 126激活的小胶质细胞合成促炎因子和趋化因子的必要条件，抑制NF-κB活化消除了PrP 106 -126诱导的NALP 3上调，PrP 106 -126诱导的小胶质细胞NALP 3炎性小体激活与钾离子外流和活性氧的产生有关。诱导小胶质细胞活化。据我们所知，这是首次发现NALP 3炎性体参与朊病毒相关炎症的有力证据。
BackgroundPrion diseases are neurodegenerative disorders characterized by the accumulation of an abnormal disease-associated prion protein, PrPSc. In prion-infected brains, activated microglia are often present in the vicinity of PrPScaggregates, and microglial activation is thought to play a key role in the pathogenesis of prion diseases. Although interleukin (IL)-1β release by prion-induced microglia has been widely reported, the mechanism by which primed microglia become activated and secrete IL-1β in prion diseases has not yet been elucidated. In this study, we investigated the role of the NACHT, LRR and PYD domains-containing protein (NALP)3 inflammasome in IL-1β release from lipopolysaccharide (LPS)-primed microglia after exposure to a synthetic neurotoxic prion fragment (PrP106-126).MethodsThe inflammasome components NALP3 and apoptosis-associated speck-like protein (ASC) were knocked down by gene silencing. IL-1β production was assessed using ELISA. The mRNA expression of NALP3, ASC, and pro-inflammatory factors was measured by quantitative PCR. Western blot analysis was used to detect the protein level of NALP3, ASC, caspase-1 and nuclear factor-κB.ResultsWe found that that PrP106-126-induced IL-1β release depends on NALP3 inflammasome activation, that inflammasome activation is required for the synthesis of pro-inflammatory and chemotactic factors by PrP106-126-activated microglia, that inhibition of NF-κB activation abrogated PrP106-126-induced NALP3 upregulation, and that potassium efflux and production of reactive oxygen species were implicated in PrP106-126-induced NALP3 inflammasome activation in microglia.ConclusionsWe conclude that the NALP3 inflammasome is involved in neurotoxic prion peptide-induced microglial activation. To our knowledge, this is the first time that strong evidence for the involvement of NALP3 inflammasome in prion-associated inflammation has been found.