Kessing Cari F, Tyor William R
1 Department of Neurology, Emory University School of Medicine , Atlanta, Georgia .
J Interferon Cytokine Res. 2015 Apr;35(4):317-24. doi: 10.1089/jir.2014.0105. Epub 2014 Dec 17.
Elevated levels of interferon-alpha (IFNα) in the central nervous system (CNS) are linked to cognitive dysfunction in patients with inflammatory CNS diseases such as HIV-associated neurocognitive disorders (HAND). Increased CNS IFNα has also been found to be associated with cognitive dysfunction in a HAND mouse model. Here, we corroborate previous studies showing a dose-dependent decrease in dendritic branching and length caused by IFNα treatment and extend those studies. Because both direct and indirect mechanisms of IFNα-induced neurotoxicity are likely involved, the cell signaling pathway involving the IFNα receptor (IFNAR) was initially evaluated. Rat neuronal cultures exposed to IFNα demonstrate increased phosphorylation of STAT1 and increased interferon stimulating gene 15 (ISG15) expression, indicators of IFNAR engagement. However, specific blocking antibodies to the IFNAR were found to only partially protect neurons from IFNα-induced neurotoxicity. Additionally, inhibiting the GluN2A subunit of N-methyl-D-asparate receptor (NMDAR) was also found to be partially protective against IFNα-induced neurotoxicity compared with the GluN2B subunit. Neurotoxicity is evident in neurons extracted from IFNAR KO mice treated with IFNα as well, further indicating that IFNAR signaling is not required for IFNα neurotoxicity. The neurotoxic actions of IFNα are mediated through both the IFNAR as well as the GluN2A subunit of the NMDAR to reduce dendritic arborization in neurons. Complete protection from IFNα-induced neurotoxicity was demonstrated when both pathways were blocked. Blocking these pathways could lead to potential therapies for cognitive dysfunction during neuroinflammation and specifically lead to better treatments for HAND.
中枢神经系统（CNS）中α-干扰素（IFNα）水平升高与炎症性中枢神经系统疾病患者的认知功能障碍有关，如人类免疫缺陷病毒相关神经认知障碍（HAND）。在HAND小鼠模型中也发现中枢神经系统IFNα升高与认知功能障碍有关。在此，我们证实了先前的研究，即IFNα处理会导致树突分支和长度呈剂量依赖性减少，并扩展了这些研究。由于IFNα诱导神经毒性的直接和间接机制可能都涉及其中，因此最初评估了涉及IFNα受体（IFNAR）的细胞信号通路。暴露于IFNα的大鼠神经元培养物显示信号转导和转录激活因子1（STAT1）磷酸化增加以及干扰素刺激基因15（ISG15）表达增加，这是IFNAR参与的指标。然而，发现针对IFNAR的特异性阻断抗体只能部分保护神经元免受IFNα诱导的神经毒性。此外，与谷氨酸受体2B（GluN2B）亚基相比，抑制N-甲基-D-天冬氨酸受体（NMDAR）的谷氨酸受体2A（GluN2A）亚基也被发现对IFNα诱导的神经毒性有部分保护作用。在用IFNα处理的IFNAR基因敲除（KO）小鼠提取的神经元中也明显存在神经毒性，这进一步表明IFNα神经毒性不需要IFNAR信号传导。IFNα的神经毒性作用是通过IFNAR以及NMDAR的GluN2A亚基介导的，以减少神经元中的树突分支。当两条通路都被阻断时，证明对IFNα诱导的神经毒性具有完全保护作用。阻断这些通路可能会为神经炎症期间的认知功能障碍带来潜在的治疗方法，特别是为HAND带来更好的治疗方法。
