Amyloid β directly interacts with NLRP3 to initiate inflammasome activation: identification of an intrinsic NLRP3 ligand in a cell-free system.
Amyloid β directly interacts with NLRP3 to initiate inflammasome activation: identification of an intrinsic NLRP3 ligand in a cell-free system.
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DOI：
10.1186/s41232-018-0085-6
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发表时间：
2018
影响因子：
8.1
通讯作者：
Masumoto J
中科院分区：
文献类型：
--
作者：
Nakanishi A;Kaneko N;Takeda H;Sawasaki T;Morikawa S;Zhou W;Kurata M;Yamamoto T;Akbar SMF;Zako T;Masumoto J
阿尔茨海默病是一种以β淀粉样蛋白（a β）斑块间质沉积为特征的神经退行性疾病，被认为与慢性神经炎症有关。已知Aβ通过单体的低聚物产生原纤维。据报道，Aβ可激活浸润性巨噬细胞中的NLRP3炎性体。NLRP3是一种细胞内模式识别受体，据报道可以识别许多病原体和/或代谢物，并与受体蛋白ASC形成复合物，形成炎性小体，这是一种白细胞介素(IL)-1β加工平台。尽管已有报道称线粒体中的活性氧参与了Aβ沉积时小胶质细胞中NLRP3炎性小体的激活，但Aβ是否直接或间接激活NLRP3炎性小体尚不清楚。我们制备了a β单体、低聚物和原纤维，促进了NLRP3与每种形式的a β的相互作用，并在无细胞系统中利用放大发光接近均相法分析了每种形式的a β诱导的NLRP3与ASC的相互作用。我们还通过使用人胚胎肾293T细胞和人外周单核细胞的细胞基础实验证实了生理相关性。成功地制备了Aβ的单体、低聚物和原纤维。Aβ低聚物和原纤维与NLRP3相互作用。Aβ低聚物和原纤维诱导NLRP3与ASC相互作用。然而，在无细胞系统中，Aβ单体不与NLRP3相互作用，也不诱导NLRP3与ASC相互作用，并且根据基于细胞的实验，IL-1β不分泌。来自无毒Aβ单体的寡聚Aβ直接与NLRP3相互作用，导致NLRP3炎性体的激活。这可能是治疗阿尔茨海默病的一个有吸引力的靶点。本文的在线版本（10.1186/s41232-018-0085-6）包含补充材料，仅供授权用户使用。
Alzheimer’s disease is a neurodegenerative disease characterized by the interstitial deposition of amyloid β (Aβ) plaque, which is thought to be related to chronic neuroinflammation. Aβ is known to make fibrils via oligomers from monomers. Aβ has been reported to activate the NLRP3 inflammasome in infiltrated macrophages. NLRP3, an intracellular pattern recognition receptor, has been reported to recognize numerous pathogens and/or metabolites and form complexes with adopter protein ASC to make the inflammasome, an interleukin (IL)-1β-processing platform. Although reactive oxygen species from mitochondria have been reported to be involved in the activation of the NLRP3 inflammasome in microglial cells upon the deposition of Aβ, whether Aβ directly or indirectly activates the NLRP3 inflammasome remains unclear. We prepared monomers, oligomers, and fibrils of Aβ, which promoted the interaction between NLRP3 and each form of Aβ and analyzed the interaction between NLRP3 and ASC induced by each form of Aβ in a cell-free system with the amplified luminescent proximity homogeneous assay. We also confirmed the physiological relevance in a cell-based assay using human embryonic kidney 293T cells and human peripheral mononuclear cells. Monomers, oligomers, and fibrils of Aβ were successfully prepared. Aβ oligomers and fibrils interacted with NLRP3. Aβ oligomers and fibrils induced the interaction between NLRP3 and ASC. However, Aβ monomers did not interact with NLRP3 or induce interaction between NLRP3 and ASC in the cell-free system, and IL-1β was not secreted according to the cell-based assay. Oligomerized Aβ originating from non-toxic Aβ monomers directly interacted with NLRP3, leading to the activation of the NLRP3 inflammasome. This may be an attractive target for the treatment of Alzheimer’s disease. The online version of this article (10.1186/s41232-018-0085-6) contains supplementary material, which is available to authorized users.
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感知炎症体的细胞质危险信号。
影响因子：
9.1
作者：
Alnemri, Emad S.
通讯作者：
Alnemri, Emad S.
影响因子：
30.5
作者：
Franchi, Luigi;Amer, Amal;Nunez, Gabriel
通讯作者：
Nunez, Gabriel
影响因子：
30.5
作者：
通讯作者：
--
DOI：
10.1084/jem.20142384
发表时间：
2015-06-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kim ML;Chae JJ;Park YH;De Nardo D;Stirzaker RA;Ko HJ;Tye H;Cengia L;DiRago L;Metcalf D;Roberts AW;Kastner DL;Lew AM;Lyras D;Kile BT;Croker BA;Masters SL
通讯作者：
Masters SL
影响因子：
5.3
作者：
Salminen A;Ojala J;Suuronen T;Kaarniranta K;Kauppinen A
通讯作者：
Kauppinen A