Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan; Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital, Linkou, Taiwan.
Department of Anatomy, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Mol Cell Neurosci. 2023 Jun;125:103848. doi: 10.1016/j.mcn.2023.103848. Epub 2023 Mar 21.
Astrocytes are key players in neuroinflammation. In response to central nervous system (CNS) injury or disease, astrocytes undergo reactive astrogliosis, which is characterized by increased proliferation, migration, and glial fibrillary acidic protein (GFAP) expression. Activation of the transcription factor nuclear factor-κB (NF-κB) and upregulation of downstream proinflammatory mediators in reactive astrocytes induce a proinflammatory phenotype in astrocytes, thereby exacerbating neuroinflammation by establishing an inflammatory loop. In this study, we hypothesized that excessive fibronectin (FN) derived from reactive astrocytes would induce this proinflammatory phenotype in astrocytes in an autocrine manner. We exogenously treated astrocytes with monomer FN, which can be incorporated into the extracellular matrix (ECM), to mimic plasma FN extravasated through a compromised blood-brain barrier in neuroinflammation. We also induced de novo synthesis and accumulation of astrocyte-derived FN through tumor necrosis factor-α (TNF-α) stimulation. The excessive FN deposition resulting from both treatments initiated reactive astrogliosis and triggered NF-κB signaling in the cultured astrocytes. In addition, inhibition of FN accumulation in the ECM by the FN inhibitor pUR4 strongly attenuated the FN- and TNF-α-induced GFAP expression, NF-κB activation, and proinflammatory mediator production of astrocytes by interrupting FN-β1 integrin coupling and thus the inflammatory loop. In an in vivo experiment, intrathecal injection of pUR4 considerably ameliorated FN deposition, GFAP expression, and NF-κB activation in inflamed spinal cord, suggesting the therapeutic potential of pUR4 for attenuating neuroinflammation and promoting neuronal function restoration.
星形胶质细胞是神经炎症的关键参与者。在中枢神经系统 (CNS) 损伤或疾病的反应中，星形胶质细胞经历反应性星形胶质细胞增生，其特征在于增殖、迁移和神经胶质纤维酸性蛋白 (GFAP) 的表达增加。转录因子核因子-κB (NF-κB) 的激活和反应性星形胶质细胞中下游促炎介质的上调诱导星形胶质细胞中促炎表型，从而通过建立炎症环加剧神经炎症。在这项研究中，我们假设来自反应性星形胶质细胞的过度纤维连接蛋白 (FN) 将以自分泌的方式诱导星形胶质细胞中的这种促炎表型。我们通过用单体 FN 处理星形胶质细胞来模拟外渗穿过神经炎症中受损血脑屏障的血浆 FN，该单体 FN 可整合到细胞外基质 (ECM) 中。我们还通过肿瘤坏死因子-α (TNF-α) 刺激诱导星形胶质细胞中 FN 的从头合成和积累。这两种处理导致的 FN 过度沉积引发反应性星形胶质细胞增生，并触发培养星形胶质细胞中的 NF-κB 信号通路。此外，FN 抑制剂 pUR4 通过抑制 FN-β1 整联蛋白偶联和炎症环来抑制 ECM 中 FN 的积累，从而强烈减弱 FN 和 TNF-α 诱导的 GFAP 表达、NF-κB 激活和星形胶质细胞促炎介质的产生。在体内实验中，鞘内注射 pUR4 可显著改善炎症性脊髓中的 FN 沉积、GFAP 表达和 NF-κB 激活，表明 pUR4 具有减弱神经炎症和促进神经元功能恢复的治疗潜力。
