Laquinimod attenuates inflammation by modulating macrophage functions in traumatic brain injury mouse model.
Laquinimod attenuates inflammation by modulating macrophage functions in traumatic brain injury mouse model.
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DOI：
10.1186/s12974-018-1075-y
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发表时间：
2018-01-30
影响因子：
9.3
通讯作者：
Lamb BT
中科院分区：
文献类型：
--
作者：
Katsumoto A;Miranda AS;Butovsky O;Teixeira AL;Ransohoff RM;Lamb BT
创伤性脑损伤（TBI）是世界范围内严重的公共卫生和社会经济问题。越来越多的证据支持炎症事件参与TBI。据报道，驻留的小胶质细胞和浸润的单核细胞促进炎症反应，导致神经元死亡并最终导致行为和认知障碍。目前，还没有有效的治疗TBI和新的治疗策略的发展是最高优先级的科学目标。拉喹莫德是一种口服神经免疫调节剂，最初用于治疗多发性硬化，可能是一种有前途的TBI神经保护治疗。在此，我们的目的是调查拉喹莫德将减少由TBI引起的中枢神经系统（CNS）损伤的假设。为了检验我们的假设，Ccr 2 rfp/+ Cx 3cr 1gfp/+小鼠被提交到由液压冲击诱导的中度TBI。假手术对照组仅进行开颅术。在TBI前7天和TBI后3天，每天通过口服管饲法用拉喹莫德（25 mg/kg）处理小鼠。在损伤后3天和120天收集用拉喹莫德治疗或未用拉喹莫德治疗的小鼠的脑，并通过显微镜分析评估脑形态学变化、轴突损伤和神经发生。我们还从浸润的单核细胞中分离出小胶质细胞，并通过采用定量NanoString nCounter技术分析免疫基因mRNA的表达。拉喹莫德可长期预防TBI引起的心室扩大。免疫组织化学分析显示，在早期阶段（损伤后3天），拉喹莫德治疗的TBI组中轴突损伤减少，神经发生恢复。值得注意的是，拉喹莫德抑制单核细胞向脑的浸润。层次聚类表明，来自用拉喹莫德处理的TBI组的小胶质细胞基因表达比TBI-水对照组更类似于假手术组。TBI后，拉喹莫德的给药减少了病变体积和轴突损伤，并恢复了神经发生。拉喹莫德可能是改善TBI长期预后的潜在治疗策略。本文的在线版本（10.1186/s12974-018-1075-y）包含补充材料，可供授权用户使用。
Traumatic brain injury (TBI) is a critical public health and socio-economic problem worldwide. A growing body of evidence supports the involvement of inflammatory events in TBI. It has been reported that resident microglia and infiltrating monocytes promote an inflammatory reaction that leads to neuronal death and eventually behavioral and cognitive impairment. Currently, there is no effective treatment for TBI and the development of new therapeutic strategies is a scientific goal of highest priority. Laquinimod, an orally administered neuroimmunomodulator initially developed for the treatment of multiple sclerosis, might be a promising neuroprotective therapy for TBI. Herein, we aim to investigate the hypothesis that laquinimod will reduce the central nervous system (CNS) damage caused by TBI. To test our hypothesis, Ccr2rfp/+ Cx3cr1gfp/+ mice were submitted to a moderate TBI induced by fluid percussion. Sham controls were submitted only to craniotomy. Mice were treated daily by oral gavage with laquinimod (25 mg/kg) 7 days before and 3 days after TBI. The brains of mice treated or not treated with laquinimod were collected at 3 and 120 days post injury, and brain morphological changes, axonal injury, and neurogenesis were evaluated by microscopy analysis. We also isolated microglia from infiltrating monocytes, and the expression of immune gene mRNAs were analyzed by employing a quantitative NanoString nCounter technique. Laquinimod prevented ventricle enlargement caused by TBI in the long term. Immunohistochemical analyses revealed decreased axonal damage and restored neurogenesis in the laquinimod-treated TBI group at early stage (3 days post injury). Notably, laquinimod inhibited the monocytes infiltration to the brain. Hierarchial clustering demonstrated that the microglial gene expression from the TBI group treated with laquinimod resembles the sham group more than the TBI-water control group. Administration of laquinimod reduced lesion volume and axonal damage and restored neurogenesis after TBI. Laquinimod might be a potential therapy strategy to improve TBI long-term prognosis. The online version of this article (10.1186/s12974-018-1075-y) contains supplementary material, which is available to authorized users.
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影响因子：
4.7
作者：
Dobson L;Träger U;Farmer R;Hayardeny L;Loupe P;Hayden MR;Tabrizi SJ
通讯作者：
Tabrizi SJ
影响因子：
11.2
作者：
Butovsky, Oleg;Jedrychowski, Mark P.;Cialic, Ron;Krasemann, Susanne;Murugaiyan, Gopal;Fanek, Zain;Greco, David J.;Wu, Pauline M.;Doykan, Camille E.;Kiner, Olga;Lawson, Robert J.;Frosch, Matthew P.;Pochet, Nathalie;El Fatimy, Rachid;Krichevsky, Anna M.;Gygi, Steven P.;Lassmann, Hans;Berry, James;Cudkowicz, Merit E.;Weiner, Howard L.
通讯作者：
Weiner, Howard L.
影响因子：
13.3
作者：
Lourenco, Elaine V.;Wong, Maida;Skaggs, Brian J.
通讯作者：
Skaggs, Brian J.
影响因子：
4.2
作者：
Hsieh, Christine L.;Niemi, Erene C.;Nakamura, Mary C.
通讯作者：
Nakamura, Mary C.
影响因子：
5.3
作者：
Jung, S;Aliberti, J;Littman, DR
通讯作者：
Littman, DR