The Ketone Body β-Hydroxybutyrate Does Not Inhibit Synuclein Mediated Inflammasome Activation in Microglia
The Ketone Body β-Hydroxybutyrate Does Not Inhibit Synuclein Mediated Inflammasome Activation in Microglia
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DOI：
10.1007/s11481-017-9754-5
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发表时间：
2017-12-01
影响因子：
6.2
通讯作者：
Gordon, Richard
中科院分区：
文献类型：
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作者：
Deora, Vandana;Albornoz, Eduardo A.;Gordon, Richard
帕金森病(Parkinson‘s Disease，PD)是公认的最常见的神经退行性运动障碍，导致衰弱的运动障碍。路易小体形式的神经毒性突触核蛋白聚集体的聚集和扩散是帕金森病的一个重要病理特征。NLRP3炎症体的慢性激活是进行性神经退行性疾病的主要致病机制，被认为是一个重要的治疗靶点。最近，酮体，β-羟基丁酸酯(BHB)，被证明有效地抑制巨噬细胞中的NLRP3炎症体，以及体内的炎症性疾病模型。此外，BHB可以很容易地穿过血脑屏障，这表明它可能对帕金森病的治疗有好处。在这项研究中，我们评估了BHB是否可以抑制由病理性纤维突触核蛋白聚集体诱导的慢性小胶质细胞炎症小体激活。有趣的是，我们发现BHB治疗几乎完全阻断了由ATP和尿酸一钠(MSU)晶体诱导的炎性小体激活和下垂的所有方面，这与先前在巨噬细胞中发表的报告一致。然而，令人惊讶的是，BHB并没有抑制由突触核蛋白纤维诱导的炎症体的激活和IL-1β或caspase-1的释放。我们的研究结果表明，BHB并不阻断由突触核蛋白纤维调节炎症小体激活的上游通路，并提示与传统的NLRP3激活剂如ATP和MSU相比，突触核蛋白介导的炎性小体激活是通过不同的机制进行的。
Parkinson's disease (PD) is recognized as the most common neurodegenerative movement disorder and results in debilitating motor deficits. The accumulation and spread of neurotoxic synuclein aggregates in the form of Lewy bodies is a key pathological feature of PD. Chronic activation of the NLRP3 inflammasome by protein aggregates is emerging as a major pathogenic mechanism in progressive neurodegenerative disorders and is considered an important therapeutic target. Recently the ketone body, beta-hydroxy butyrate (BHB), was shown to efficiently inhibit the NLRP3 inflammasome in macrophages, and in vivo models of inflammatory disease. Furthermore, BHB can readily cross the blood brain barrier suggesting that it could have therapeutic benefits for the management of PD. In this study, we evaluated if BHB could inhibit chronic microglial inflammasome activation induced by pathological fibrillar synuclein aggregates. Interestingly, we found that BHB treatment almost completely blocked all aspects of inflammasome activation and pyroptosis induced by ATP and monosodium urate (MSU) crystals, consistent with previously published reports in macrophages. Surprisingly however, BHB did not inhibit inflammasome activation and release of IL-1 beta or caspase-1 induced by synuclein fibrils. Our results demonstrate that BHB does not block the upstream pathways regulating inflammasome activation by synuclein fibrils and suggest that synuclein mediated inflammasome activation proceeds via distinct mechanisms compared to traditional NLRP3 activators such as ATP and MSU.