Department of Biochemistry and Immunology, Institute of Biological Sciences (ICB), Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Department of Morphology, Institute of Biological Sciences (ICB), Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Front Immunol. 2023 Dec 11;14:1283331. doi: 10.3389/fimmu.2023.1283331. eCollection 2023.
TNF-α is essential for induction and maintenance of inflammatory responses and its dysregulation is associated with susceptibility to various pathogens that infect the central nervous system. Activation of both microglia and astrocytes leads to TNF-α production, which in turn triggers further activation of these cells. Astrocytes have been implicated in the pathophysiology of a wide range of neurodegenerative diseases with either harmful or protective roles, as these cells are capable of secreting several inflammatory factors and also promote synapse elimination and remodeling. These responses are possible because they sense their surroundings via several receptors, including the metabotropic glutamate receptor 5 (mGluR5). Under neuroinflammatory conditions, mGluR5 activation in astrocytes can be neuroprotective or have the opposite effect. In the current study, we investigated the role of mGluR5 in hiPSC-derived astrocytes subjected to pro-inflammatory stimulation by recombinant TNF-α (rTNF-α). Our results show that mGluR5 blockade by CTEP decreases the secreted levels of pro-inflammatory cytokines (IL-6 and IL-8) following short rTNF-α stimulation, although this effect subsides with time. Additionally, CTEP enhances synaptoneurosome phagocytosis by astrocytes in both non-stimulated and rTNF-α-stimulated conditions, indicating that mGluR5 blockade alone is enough to drive synaptic material engulfment. Finally, mGluR5 antagonism as well as rTNF-α stimulation augment the expression of the reactivity marker SERPINA3 and reduces the expression of synaptogenic molecules. Altogether, these data suggest a complex role for mGluR5 in human astrocytes, since its blockade may have beneficial and detrimental effects under inflammatory conditions.
TNF-α 对于炎症反应的诱导和维持至关重要，其失调与易感性各种病原体感染中枢神经系统有关。小胶质细胞和星形胶质细胞的激活导致 TNF-α 的产生，进而触发这些细胞的进一步激活。星形胶质细胞参与了广泛的神经退行性疾病的病理生理学，具有有害或保护作用，因为这些细胞能够分泌几种炎症因子，还能促进突触消除和重塑。这些反应是可能的，因为它们通过几种受体感知周围环境，包括代谢型谷氨酸受体 5 (mGluR5)。在神经炎症条件下，星形胶质细胞中 mGluR5 的激活可能具有神经保护作用，也可能产生相反的效果。在本研究中，我们研究了 mGluR5 在 hiPSC 衍生的星形胶质细胞中在重组 TNF-α（rTNF-α）促炎刺激下的作用。我们的结果表明，mGluR5 阻断剂 CTEP 可降低短时间 rTNF-α刺激后促炎细胞因子（IL-6 和 IL-8）的分泌水平，但这种作用会随时间消退。此外，CTEP 增强了星形胶质细胞在非刺激和 rTNF-α刺激条件下吞噬突触小体的能力，表明 mGluR5 阻断本身足以驱动突触物质吞噬。最后，mGluR5 拮抗和 rTNF-α 刺激均增强了反应性标志物 SERPINA3 的表达，并降低了突触生成分子的表达。总之，这些数据表明 mGluR5 在人类星形胶质细胞中具有复杂的作用，因为在炎症条件下，其阻断可能既有有益的又有有害的影响。
