靶向 NLRP3 炎性小体介导的神经退行性疾病中的小胶质细胞自噬降解。
Targeting microglial autophagic degradation in NLRP3 inflammasome-mediated neurodegenerative diseases.
机构信息
Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy; Education Ministry Key Laboratory of Medical Electrophysiology; College of Preclinical Medicine, Southwest Medical University, Luzhou, 646000, China.
Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy; Education Ministry Key Laboratory of Medical Electrophysiology; College of Preclinical Medicine, Southwest Medical University, Luzhou, 646000, China; State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, 999078, China.
出版信息
Ageing Res Rev. 2021 Jan;65:101202. doi: 10.1016/j.arr.2020.101202. Epub 2020 Nov 5.
Neuroinflammation is considered as a detrimental factor in neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), etc. Nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3), the most well-studied inflammasome, is abundantly expressed in microglia and has gained considerable attention. Misfolded proteins are characterized as the common hallmarks of neurodegenerative diseases due to not only their induced neuronal toxicity but also their effects in over-activating microglia and the NLRP3 inflammasome. The activated NLRP3 inflammasome aggravates the pathology and accelerates the progression of neurodegenerative diseases. Emerging evidence indicates that microglial autophagy plays an important role in the maintenance of brain homeostasis and the negative regulation of NLRP3 inflammasome-mediated neuroinflammation. The excessive activation of NLRP3 inflammasome impairs microglial autophagy and further aggravates the pathogenesis of neurodegenerative diseases. In this review article, we summarize and discuss the NLRP3 inflammasome and its specific inhibitors in microglia. The crucial role of microglial autophagy and its inducers in the removal of misfolded proteins, the clearance of damaged mitochondria and reactive oxygen species (ROS), and the degradation of the NLRP3 inflammasome or its components in neurodegenerative diseases are summarized. Understanding the underlying mechanisms behind the sex differences in NLRP3 inflammasome-mediated neurodegenerative diseases will help researchers to develop more targeted therapies and increase our diagnostic and prognostic abilities. In addition, the superiority of the combined use of microglial autophagy inducers with the specific inhibitors of the NLRP3 inflammasome in the inhibition of NLRP3 inflammasome-mediated neuroinflammation requires further preclinical and clinical validations in the future.
神经炎症被认为是神经退行性疾病的有害因素，包括阿尔茨海默病（AD）、帕金森病（PD）、亨廷顿病（HD）等。核苷酸结合寡聚化结构域、富含亮氨酸重复和吡喃结构域蛋白 3（NLRP3）是研究最为广泛的炎性小体，在小胶质细胞中大量表达，受到了广泛关注。由于错误折叠蛋白不仅诱导神经元毒性，而且还能过度激活小胶质细胞和 NLRP3 炎性小体，因此它们是神经退行性疾病的共同特征。激活的 NLRP3 炎性小体加重了神经退行性疾病的病理学并加速了其进展。新出现的证据表明，小胶质细胞自噬在维持大脑内稳态和负调控 NLRP3 炎性小体介导的神经炎症中发挥着重要作用。NLRP3 炎性小体的过度激活会损害小胶质细胞自噬，从而进一步加重神经退行性疾病的发病机制。在这篇综述文章中，我们总结和讨论了 NLRP3 炎性小体及其在小胶质细胞中的特异性抑制剂。小胶质细胞自噬及其诱导剂在清除错误折叠蛋白、清除受损线粒体和活性氧（ROS）以及降解 NLRP3 炎性小体或其成分方面的重要作用，在神经退行性疾病中得到了总结。了解 NLRP3 炎性小体介导的神经退行性疾病中性别差异的潜在机制将有助于研究人员开发更有针对性的治疗方法，并提高我们的诊断和预测能力。此外，在未来，还需要进一步的临床前和临床验证，以确定小胶质细胞自噬诱导剂与 NLRP3 炎性小体特异性抑制剂联合使用在抑制 NLRP3 炎性小体介导的神经炎症方面的优越性。
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