SOD1(G93A) transgenic mouse CD4(+) T cells mediate neuroprotection after facial nerve axotomy when removed from a suppressive peripheral microenvironment.
SOD1(G93A) transgenic mouse CD4(+) T cells mediate neuroprotection after facial nerve axotomy when removed from a suppressive peripheral microenvironment.
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DOI：
10.1016/j.bbi.2014.05.019
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发表时间：
2014-08
影响因子：
15.1
通讯作者：
Jones, Kathryn J.
中科院分区：
文献类型：
--
作者：
Mesnard-Hoaglin, Nichole A.;Xin, Junping;Haulcomb, Melissa M.;Batka, Richard J.;Sanders, Virginia M.;Jones, Kathryn J.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，涉及运动神经元（MN）轴突退缩和细胞死亡。先前，我们建立了SOD1G93A转基因ALS小鼠模型中面部MN （FMN）存活水平降低，神经再生延迟，与免疫缺陷的RAG2-/-小鼠相似。本研究的目的是研究SOD1G93A脾微环境的功能，重点关注CD4+ T细胞在免疫介导的损伤MN神经保护缺陷中的作用。我们利用RAG2-/-和SOD1G93A小鼠模型，以及面神经轴切范式和各种细胞过继转移，来评估免疫介导的FMN存活水平的神经保护作用。我们确定过继性转移SOD1G93A未分离脾细胞到RAG2-/-小鼠中不能支持肛切开术后FMN的存活，但过继性转移分离SOD1G93A CD4+ T细胞可以。虽然过继转移到SOD1G93A小鼠的WT未分离脾细胞能够维持FMN存活水平，但单独WT CD4+ T细胞不能维持FMN存活水平。重要的是，这些结果表明，当从功能失调的SOD1G93A外周脾微环境中移除时，SOD1G93A CD4+ T细胞保留了神经保护功能。这些结果还表明，当允许的外周微环境存在时，SOD1G93A中枢神经系统微环境能够重新激活CD4+ T细胞进行免疫介导的神经保护。我们假设功能失调的SOD1G93A外周脾微环境可能会损害神经保护性CD4+ T细胞的活化和/或分化，进而导致SOD1G93A小鼠外周轴切术后免疫介导的MN存活神经保护受损。
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving motoneuron (MN) axonal withdrawal and cell death. Previously, we established that facial MN (FMN) survival levels in the SOD1G93A transgenic mouse model of ALS are reduced and nerve regeneration is delayed, similar to immunodeficient RAG2-/- mice, after facial nerve axotomy. The objective of this study was to examine the functionality of SOD1G93A splenic microenvironment, focusing on CD4+ T cells, with regard to defects in immune-mediated neuroprotection of injured MN. We utilized the RAG2-/- and SOD1G93A mouse models, along with the facial nerve axotomy paradigm and a variety of cellular adoptive transfers, to assess immune-mediated neuroprotection of FMN survival levels. We determined that adoptively transferred SOD1G93A unfractionated splenocytes into RAG2-/- mice were unable to support FMN survival after axotomy, but that adoptive transfer of isolated SOD1G93A CD4+ T cells could. Although WT unfractionated splenocytes adoptively transferred into SOD1G93A mice were able to maintain FMN survival levels, WT CD4+ T cells alone could not. Importantly, these results suggest that SOD1G93A CD4+ T cells retain neuroprotective functionality when removed from a dysfunctional SOD1G93A peripheral splenic microenvironment. These results also indicate that the SOD1G93A central nervous system microenvironment is able to re-activate CD4+ T cells for immune-mediated neuroprotection when a permissive peripheral microenvironment exists. We hypothesize that dysfunctional SOD1G93A peripheral splenic microenvironment may compromise neuroprotective CD4+ T cell activation and/or differentiation, which, in turn, results in impaired immune-mediated neuroprotection for MN survival after peripheral axotomy in SOD1G93A mice.
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