Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
J Leukoc Biol. 2018 Nov;104(5):961-968. doi: 10.1002/JLB.MA1217-484R. Epub 2018 Jul 25.
Proinflammatory TNF-α facilitates dengue virus (DENV) infection in endovascular dysfunction and neurotoxicity. The introduction of TNF-α blocking therapy with Abs is performed to test its therapeutic effect in this study. In DENV-infected mice, TNF-α production in the brain accompanied the progression of neurotoxicity and encephalitis. DENV infection caused the loss of hippocampal neurons with TNF-α expression around damaged regions, and immunostaining showed the induction of apoptosis in hippocampal neurons. TNF-α was expressed in active microglia and astrocytes in DENV-infected mice. TNF-α facilitated DENV-induced neurotoxicity in vitro in murine Neuro-2a cells. Using a currently established encephalitic mouse model in which DENV infection causes progressive hunchback posture, limbic seizures, limbic weakness, paralysis, and lethality 7 days postinfection, we showed that TNF-α transgenic mice represented the progressive disease development and administration of neutralizing TNF-α Ab reduced dengue encephalitis and mortality. These results demonstrate an immunopathogenesis of TNF-α for mediating DENV-induced encephalitis-associated neurotoxicity and that targeting TNF-α can be used as a strategy against dengue encephalitis.
促炎细胞因子 TNF-α 促进血管内功能障碍和神经毒性中的登革热病毒 (DENV) 感染。本研究采用 TNF-α 阻断疗法来测试其治疗效果。在 DENV 感染的小鼠中，大脑中的 TNF-α 产生伴随着神经毒性和脑炎的进展。DENV 感染导致 TNF-α 表达的海马神经元在受损区域周围丢失，免疫染色显示海马神经元发生凋亡。TNF-α在 DENV 感染的小鼠中的活性小胶质细胞和星形胶质细胞中表达。TNF-α 促进了体外鼠 Neuro-2a 细胞中 DENV 诱导的神经毒性。利用目前建立的脑炎小鼠模型，其中 DENV 感染导致感染后 7 天出现渐进性驼背姿势、边缘性癫痫发作、边缘性无力、瘫痪和致死性，我们表明 TNF-α 转基因小鼠表现出进行性疾病发展，中和 TNF-α 的 Ab 给药可减少登革热脑炎和死亡率。这些结果表明 TNF-α 的免疫发病机制可介导 DENV 诱导的脑炎相关神经毒性，针对 TNF-α 可作为对抗登革热脑炎的策略。
