Subbarayan Meena S, Joly-Amado Aurelie, Bickford Paula C, Nash Kevin R
Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa FL-33612, USA; Center for Excellence in Aging and Brain Repair, Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa FL-33612, USA.
Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa FL-33612, USA.
Pharmacol Ther. 2022 Mar;231:107989. doi: 10.1016/j.pharmthera.2021.107989. Epub 2021 Sep 4.
Neuroinflammation was initially thought of as a consequence of neurodegenerative disease pathology, but more recently it is becoming clear that it plays a significant role in the development and progression of disease. Thus, neuroinflammation is seen as a realistic and valuable therapeutic target for neurodegeneration. Neuroinflammation can be modulated by neuron-glial signaling through various soluble factors, and one such critical modulator is Fractalkine or C-X3-C Motif Chemokine Ligand 1 (CX3CL1). CX3CL1 is produced in neurons and is a unique chemokine that is initially translated as a transmembrane protein but can be proteolytically processed to generate a soluble chemokine. CX3CL1 has been shown to signal through its sole receptor CX3CR1, which is located on microglial cells within the central nervous system (CNS). Although both the membrane bound and soluble forms of CX3CL1 appear to interact with CX3CR1, they do seem to have different signaling capabilities. It is believed that the predominant function of CX3CL1 within the CNS is to reduce the proinflammatory response and many studies have shown neuroprotective effects. However, in some cases CX3CL1 appears to be promoting neurodegeneration. This review focusses on presenting a comprehensive overview of the complex nature of CX3CL1/CX3CR1 signaling in neurodegeneration and how it may present as a therapeutic in some neurodegenerative diseases but not others. The role of CX3CL1/CXCR1 is reviewed in the context of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), ischemia, retinopathies, spinal cord and neuropathic pain, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis, and epilepsy.
神经炎症最初被认为是神经退行性疾病病理的结果，但最近越来越清楚的是，它在疾病的发生和发展中起着重要作用。因此，神经炎症被视为神经退行性变一个切实可行且有价值的治疗靶点。神经炎症可通过各种可溶性因子经神经元-胶质细胞信号传导进行调节，而一种关键的调节因子是 fractalkine 或 C-X3-C 基序趋化因子配体 1（CX3CL1）。CX3CL1 在神经元中产生，是一种独特的趋化因子，最初被翻译为跨膜蛋白，但可经蛋白水解加工生成可溶性趋化因子。CX3CL1 已被证明通过其唯一的受体 CX3CR1 发出信号，CX3CR1 位于中枢神经系统（CNS）内的小胶质细胞上。尽管 CX3CL1 的膜结合形式和可溶性形式似乎都与 CX3CR1 相互作用，但它们的信号传导能力似乎有所不同。据信，CX3CL1 在中枢神经系统中的主要功能是减少促炎反应，许多研究已显示其具有神经保护作用。然而，在某些情况下，CX3CL1 似乎会促进神经退行性变。本综述着重全面概述 CX3CL1/CX3CR1 信号传导在神经退行性变中的复杂性质，以及它如何在某些神经退行性疾病中但并非在其他疾病中表现为一种治疗手段。在阿尔茨海默病（AD）、帕金森病（PD）、亨廷顿病（HD）、缺血、视网膜病变、脊髓和神经性疼痛、创伤性脑损伤、肌萎缩侧索硬化、多发性硬化和癫痫的背景下，对 CX3CL1/CXCR1 的作用进行了综述。
