Chen Yvonne, Mateski Julia, Gerace Linda, Wheeler Jonathan, Burl Jan, Prakash Bhavna, Svedin Cherie, Amrick Rebecca, Adams Brian D
Department of Biology, Brandeis University, Waltham, MA, United States.
Department of RNA Sciences, The Brain Institute of America, New Haven, CT, United States.
Exp Biol Med (Maywood). 2024 Feb 28;249:10120. doi: 10.3389/ebm.2024.10120. eCollection 2024.
Neuroinflammation is considered a balanced inflammatory response important in the intrinsic repair process after injury or infection. Under chronic states of disease, injury, or infection, persistent neuroinflammation results in a heightened presence of cytokines, chemokines, and reactive oxygen species that result in tissue damage. In the CNS, the surrounding microglia normally contain macrophages and other innate immune cells that perform active immune surveillance. The resulting cytokines produced by these macrophages affect the growth, development, and responsiveness of the microglia present in both white and gray matter regions of the CNS. Controlling the levels of these cytokines ultimately improves neurocognitive function and results in the repair of lesions associated with neurologic disease. MicroRNAs (miRNAs) are master regulators of the genome and subsequently control the activity of inflammatory responses crucial in sustaining a robust and acute immunological response towards an acute infection while dampening pathways that result in heightened levels of cytokines and chemokines associated with chronic neuroinflammation. Numerous reports have directly implicated miRNAs in controlling the abundance and activity of interleukins, TGF-B, NF-kB, and toll-like receptor-signaling intrinsically linked with the development of neurological disorders such as Parkinson's, ALS, epilepsy, Alzheimer's, and neuromuscular degeneration. This review is focused on discussing the role miRNAs play in regulating or initiating these chronic neurological states, many of which maintain the level and/or activity of neuron-specific secondary messengers. Dysregulated miRNAs present in the microglia, astrocytes, oligodendrocytes, and epididymal cells, contribute to an overall glial-specific inflammatory niche that impacts the activity of neuronal conductivity, signaling action potentials, neurotransmitter robustness, neuron-neuron specific communication, and neuron-muscular connections. Understanding which miRNAs regulate microglial activation is a crucial step forward in developing non-coding RNA-based therapeutics to treat and potentially correct the behavioral and cognitive deficits typically found in patients suffering from chronic neuroinflammation.
神经炎症被认为是一种平衡的炎症反应，在损伤或感染后的内在修复过程中很重要。在疾病、损伤或感染的慢性状态下，持续的神经炎症会导致细胞因子、趋化因子和活性氧的大量存在，从而导致组织损伤。在中枢神经系统中，周围的小胶质细胞通常包含巨噬细胞和其他先天免疫细胞，它们进行主动免疫监视。这些巨噬细胞产生的细胞因子会影响中枢神经系统白质和灰质区域中存在的小胶质细胞的生长、发育和反应性。控制这些细胞因子的水平最终会改善神经认知功能，并导致与神经疾病相关的病变修复。微小RNA（miRNA）是基因组的主要调节因子，随后控制炎症反应的活性，这对于维持对急性感染的强烈而急性的免疫反应至关重要，同时抑制导致与慢性神经炎症相关的细胞因子和趋化因子水平升高的途径。许多报告直接表明，miRNA在控制白细胞介素、转化生长因子-β、核因子-κB和Toll样受体信号传导的丰度和活性方面发挥作用，这些信号传导与帕金森病、肌萎缩侧索硬化症、癫痫、阿尔茨海默病和神经肌肉变性等神经疾病的发展有着内在联系。本综述重点讨论miRNA在调节或引发这些慢性神经状态中所起的作用，其中许多慢性神经状态维持神经元特异性第二信使的水平和/或活性。小胶质细胞、星形胶质细胞、少突胶质细胞和附睾细胞中失调的miRNA，促成了一个整体的胶质细胞特异性炎症微环境，影响神经元传导性、信号动作电位、神经递质稳定性、神经元-神经元特异性通讯和神经元-肌肉连接的活性。了解哪些miRNA调节小胶质细胞的激活是开发基于非编码RNA的疗法以治疗并可能纠正慢性神经炎症患者通常出现的行为和认知缺陷的关键一步。
