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Potential neurotoxic activity of diverse molecules released by astrocytes

神经保护 细胞生物学 神经炎症 小胶质细胞 星形胶质细胞 趋化因子 化学 基质金属蛋白酶 炎症 神经退行性变 肿瘤坏死因子α 神经毒性 免疫系统 生物 免疫学 生物化学 神经科学 中枢神经系统 医学 内科学 有机化学 毒性 疾病
作者
Taryn E. Murray,Christy M. Richards,Victoria N. Robert-Gostlin,Anna K. Bernath,Ivan A. Lindhout,Andis Klegeris
出处
期刊:Brain Research Bulletin [Elsevier]
卷期号:189: 80-101 被引量:14
标识
DOI:10.1016/j.brainresbull.2022.08.015
摘要

Astrocytes are the main support cells of the central nervous system. They also participate in neuroimmune reactions. In response to pathological and immune stimuli, astrocytes transform to reactive states characterized by increased release of inflammatory mediators. Some of these molecules are neuroprotective and inflammation resolving while others, including reactive oxygen species (ROS), nitric oxide (NO), matrix metalloproteinase (MMP)− 9, L-glutamate, and tumor necrosis factor α (TNF), are well-established toxins known to cause damage to surrounding cells and tissues. We hypothesized that similar to microglia, the brain immune cells, reactive astrocytes can release a broader set of diverse molecules that are potentially neurotoxic. A literature search was conducted to identify such molecules using the following two criteria: 1) evidence of their expression and secretion by astrocytes and 2) direct neurotoxic action. This review describes 14 structurally diverse molecules as less-established astrocyte neurotoxins, including C-X-C motif chemokine ligand (CXCL)10, CXCL12/CXCL12(5−67), FS-7-associated surface antigen ligand (FasL), macrophage inflammatory protein (MIP)− 2α, TNF-related apoptosis inducing ligand (TRAIL), pro-nerve growth factor (proNGF), pro-brain-derived neurotrophic factor (proBDNF), chondroitin sulfate proteoglycans (CSPGs), cathepsin (Cat)B, group IIA secretory phospholipase A2 (sPLA2-IIA), amyloid beta peptides (Aβ), high mobility group box (HMGB)1, ceramides, and lipocalin (LCN)2. For some of these molecules, further studies are required to establish either their direct neurotoxic effects or the full spectrum of stimuli that induce their release by astrocytes. Only limited studies with human-derived astrocytes and neurons are available for most of these potential neurotoxins, which is a knowledge gap that should be addressed in the future. We also summarize available evidence of the role these molecules play in select neuropathologies where reactive astrocytes are a key feature. A comprehensive understanding of the full spectrum of neurotoxins released by reactive astrocytes is key to understanding neuroinflammatory diseases characterized by the adverse activation of these cells and may guide the development of novel treatment strategies.
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