The NLRP3-Caspase 1 Inflammasome Negatively Regulates Autophagy via TLR4-TRIF in Prion Peptide-Infected Microglia.
The NLRP3-Caspase 1 Inflammasome Negatively Regulates Autophagy via TLR4-TRIF in Prion Peptide-Infected Microglia.
复制标题
NLRP3-Caspase 1 炎症小体通过 TLR4-TRIF 在朊病毒肽感染的小胶质细胞中负向调节自噬
DOI：
10.3389/fnagi.2018.00116
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发表时间：
2018
影响因子：
4.8
通讯作者：
Yang L
中科院分区：
文献类型：
--
作者：
Lai M;Yao H;Shah SZA;Wu W;Wang D;Zhao Y;Wang L;Zhou X;Zhao D;Yang L
朊病毒疾病是神经退行性疾病，其特征在于错误折叠的朊病毒蛋白的积累、脑中的海绵状变化以及由于小胶质细胞的广泛活化而引起的脑炎症。自噬是一种高度保守的分解代谢过程，用于清除细胞质组分，包括蛋白质聚集体和受损的细胞器;该过程还消除了朊病毒感染期间积累的病理性PrPSc。NALP 3炎性体是一种多蛋白复合物，是先天免疫系统的组成部分，负责释放促炎细胞因子。我们以前的研究表明，神经毒性朊病毒肽PrP 106 -126诱导小胶质细胞中NALP 3炎性小体活化和随后的IL-1β释放。自噬参与了包括神经退行性疾病在内的许多疾病的免疫反应和炎症的调节。然而，朊病毒疾病中自噬和NALP 3炎性小体之间的关系尚未研究。在这项研究中，我们证明了成熟IL-1β的加工和释放通过抑制自噬而显著增强。相反，NALP 3炎性体的基因沉默促进自噬。通过siRNA抑制TRIF或TLR 4减弱了PrP 106 -126诱导的自噬，这表明TLR 4-TRIF信号通路参与了PrP 106 -26诱导的自噬。胱天蛋白酶1直接切割TRIF以减少TLR-4-TRIF介导的自噬。我们的研究结果表明，NALP 3炎性体抑制自噬可能是通过激活的Caspase-1诱导的TRIF切割介导的。这是第一项报道NALP 3炎性体复合物响应于小胶质细胞中PrP 106 -126刺激而负调控自噬的研究，并部分解释了Caspase-1在PrP 106 -126诱导的BV 2细胞活化中抑制自噬的机制。我们的研究结果表明，自噬上调和Caspase-1的抑制可能会防止朊病毒诱导的神经炎症和加速错误折叠的蛋白质降解，是朊病毒疾病的潜在治疗方法。
Prion diseases are neurodegenerative disorders characterized by the accumulation of misfolded prion protein, spongiform changes in the brain, and brain inflammation as a result of the wide-spread activation of microglia. Autophagy is a highly conserved catabolic process for the clearance of cytoplasmic components, including protein aggregates and damaged organelles; this process also eliminates pathological PrPSc as it accumulates during prion infection. The NALP3 inflammasome is a multiprotein complex that is a component of the innate immune system and is responsible for the release of pro-inflammatory cytokines. Our previous study showed that the neurotoxic prion peptide PrP106-126 induces NALP3 inflammasome activation and subsequent IL-1β release in microglia. Autophagy is involved in the regulation of the immune responses and inflammation in many diseases including neurodegenerative diseases. However, the relationship between autophagy and NALP3 inflammasome in prion diseases has not been investigated. In this study, we demonstrated that the processing and release of mature IL-1β is significantly enhanced by the inhibition of autophagy. Conversely, gene-silencing of the NALP3 inflammasome promotes autophagy. Suppression of TRIF or TLR4 by siRNA attenuated PrP106-126-induced autophagy, which is indicating that the TLR4-TRIF signaling pathway is involved in PrP106-26-induced autophagy. Caspase 1 directly cleaved TRIF to diminish TLR-4-TRIF mediated autophagy. Our findings suggest that the inhibition of autophagy by NALP3 inflammasome is probably mediated by activated Caspase-1-induced TRIF cleavage. This is the first study reporting that the NALP3 inflammasome complex negatively regulates autophagy in response to PrP106-126 stimulation in microglia, and partly explains the mechanism of autophagy inhibition by Caspase-1 in PrP106-126-induced BV2 cell activation. Our findings suggest that autophagy up-regulation and inhibition of Caspase-1 may protect against prion-induced neuroinflammation and accelerate misfolded protein degradation and are potential therapeutic approaches for prion diseases.
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影响因子：
11.1
作者：
He C;Klionsky DJ
通讯作者：
Klionsky DJ
影响因子：
27.4
作者：
Lin, Neng-Yu;Beyer, Christian;Distler, Joerg H. W.
通讯作者：
Distler, Joerg H. W.
影响因子：
--
作者：
Choi AJ;Ryter SW
通讯作者：
Ryter SW
影响因子：
3.7
作者：
Calil IL;Zarpelon AC;Guerrero AT;Alves-Filho JC;Ferreira SH;Cunha FQ;Cunha TM;Verri WA Jr
通讯作者：
Verri WA Jr
影响因子：
4.8
作者：
Gu, YP;Fujioka, H;Singh, N
通讯作者：
Singh, N