Amyloid-β(1-42) protofibrils stimulate a quantum of secreted IL-1β despite significant intracellular IL-1β accumulation in microglia.
Amyloid-β(1-42) protofibrils stimulate a quantum of secreted IL-1β despite significant intracellular IL-1β accumulation in microglia.
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尽管小胶质细胞中细胞内 IL-1β 积累显着，但淀粉样蛋白-β(1-42) 原纤维仍会刺激大量分泌的 IL-1β。
DOI：
10.1016/j.bbadis.2014.08.001
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发表时间：
2014-11
影响因子：
6.2
通讯作者：
Nichols, Michael R.
中科院分区：
文献类型：
--
作者：
Terrill-Usery, Shana E.;Mohan, Michael J.;Nichols, Michael R.
关键词：
神经炎症是阿尔茨海默病（AD）大脑的一个特征。在主要由β淀粉样蛋白（Aβ）组成的细胞外老年斑周围可以发现明显的炎症标志物，如活化的小胶质细胞和细胞因子。包括toll样受体（TLRs）和NLRP3炎性体在内的几种先天免疫途径与AD炎症有关。a β在激活这些通路中起主要作用，这可能导致AD的进行性神经退行性变。为了更好地理解这种相互作用的复杂性，我们研究了初级小胶质细胞对Aβ(1-42)原原纤维的炎症反应。a β(1-42)原原纤维触发了一个时间和myd88依赖的过程，产生肿瘤坏死因子α (TNFα)和白细胞介素-1β (IL-1β) mRNA，以及细胞内IL-1β蛋白的前期和成熟形式。两种IL-1β形式的积累表明，Aβ(1-42)原原纤维能够启动和激活NLRP3炎性体。令人惊讶的是，a β诱导的细胞内成熟IL-1β的积累并没有转化为更多的IL-1β分泌。相反，我们发现a β引发了分泌IL-1β的量化爆发，这一过程甚至发生在a β引发小胶质细胞之前，这表明培养的初级小胶质细胞中存在基础水平的原代或成熟IL-1β。IL-1β分泌爆发迅速，但不持久，但可通过额外的Aβ刺激重新引起。本研究结果证实了Aβ(1-42)原纤维对IL-1β的多个位点调控，包括TLR/ myd88介导的启动、NLRP3炎性体激活和IL-1β分泌过程的调节。这些结果强调了Aβ对先天免疫反应的广泛影响。
Neuroinflammation is a characteristic feature of the Alzheimer’s disease (AD) brain. Significant inflammatory markers such as activated microglia and cytokines can be found surrounding the extracellular senile plaques predominantly composed of amyloid-β protein (Aβ). Several innate immune pathways, including Toll-like receptors (TLRs) and the NLRP3 inflammasome, have been implicated in AD inflammation. Aβ plays a primary role in activating these pathways which likely contributes to the progressive neurodegeneration in AD. In order to better understand the complexities of this interaction we investigated the inflammatory response of primary microglia to Aβ(1–42) protofibrils. Aβ(1–42) protofibrils triggered a time- and MyD88-dependent process that produced tumor necrosis factor alpha (TNFα) and interleukin-1β (IL-1β) mRNA, and intracellular pro and mature forms of IL-1β protein. The accumulation of both IL-1β forms indicated that Aβ(1–42) protofibrils were able to prime and activate the NLRP3 inflammasome. Surprisingly, Aβ-induced accumulation of intracellular mature IL-1β did not translate into greater IL-1β secretion. Instead, we found that Aβ elicited a quantized burst of secreted IL-1β and this process occurred even prior to Aβ priming of the microglia suggesting a basal level of either pro or mature IL-1β in the cultured primary microglia. The IL-1β secretion burst was rapid but not sustained, yet could be re-evoked with additional Aβ stimulation. The findings from this study demonstrated multiple sites of IL-1β regulation by Aβ(1–42) protofibrils including TLR/MyD88-mediated priming, NLRP3 inflammasome activation, and modulation of the IL-1β secretory process. These results underscore the wide-ranging effects of Aβ on the innate immune response.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
16.8
作者：
Hanamsagar R;Hanke ML;Kielian T
通讯作者：
Kielian T
影响因子：
5
作者：
Paranjape, Geeta S.;Gouwens, Lisa K.;Nichols, Michael R.
通讯作者：
Nichols, Michael R.
DOI：
10.1523/jneurosci.3537-10.2010
发表时间：
2010-10-27
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
O'Nuallain B;Freir DB;Nicoll AJ;Risse E;Ferguson N;Herron CE;Collinge J;Walsh DM
通讯作者：
Walsh DM
影响因子：
4.4
作者：
Liu, Shirong;Liu, Yang;Fassbender, Klaus
通讯作者：
Fassbender, Klaus