Department of Physiology, School of Medicine and Dentistry, University of Valencia, Valencia, Spain.
Alzheimer's Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
IUBMB Life. 2021 Jul;73(7):900-915. doi: 10.1002/iub.2510. Epub 2021 Jun 4.
Toll-like receptors (TLRs) or pattern recognition receptors respond to pathogen-associated molecular patterns (PAMPs) or internal damage-associated molecular patterns (DAMPs). TLRs are integral membrane proteins with both extracellular leucine-rich and cytoplasmic domains that initiate downstream signaling through kinases by activating transcription factors like AP-1 and NF-κB, which lead to the release of various inflammatory cytokines and immune modulators. In the central nervous system, different TLRs are expressed mainly in microglia and astroglial cells, although some TLRs are also expressed in oligodendroglia and neurons. Activation of TLRs triggers signaling cascades by the host as a defense mechanism against invaders to repair damaged tissue. However, overactivation of TLRs disrupts the sustained immune homeostasis-induced production of pro-inflammatory molecules, such as cytokines, miRNAs, and inflammatory components of extracellular vesicles. These inflammatory mediators can, in turn, induce neuroinflammation, and neural tissue damage associated with many neurodegenerative diseases. This review discusses the critical role of TLRs response in Alzheimer's disease, Parkinson's disease, ischemic stroke, amyotrophic lateral sclerosis, and alcohol-induced brain damage and neurodegeneration.
Toll 样受体（TLRs）或模式识别受体对病原体相关分子模式（PAMPs）或内部损伤相关分子模式（DAMPs）作出反应。TLRs 是整合膜蛋白，具有胞外富含亮氨酸的结构域和胞质结构域，通过激活转录因子如 AP-1 和 NF-κB，启动下游信号转导，从而导致各种炎症细胞因子和免疫调节剂的释放。在中枢神经系统中，不同的 TLR 主要在小胶质细胞和星形胶质细胞中表达，尽管一些 TLR 也在少突胶质细胞和神经元中表达。TLRs 的激活触发了宿主的信号级联反应，作为一种防御机制来对抗入侵者，以修复受损组织。然而，TLRs 的过度激活会破坏持续的免疫稳态，导致促炎分子（如细胞因子、miRNA 和细胞外囊泡的炎症成分）的过度产生。这些炎症介质反过来又会引起神经炎症和与许多神经退行性疾病相关的神经组织损伤。本文综述了 TLR 反应在阿尔茨海默病、帕金森病、缺血性中风、肌萎缩侧索硬化和酒精性脑损伤和神经退行性变中的关键作用。
