Astrocyte matricellular proteins that control excitatory synaptogenesis are regulated by inflammatory cytokines and correlate with paralysis severity during experimental autoimmune encephalomyelitis.
Astrocyte matricellular proteins that control excitatory synaptogenesis are regulated by inflammatory cytokines and correlate with paralysis severity during experimental autoimmune encephalomyelitis.
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DOI：
10.3389/fnins.2015.00344
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发表时间：
2015
影响因子：
4.3
通讯作者：
Irani DN
中科院分区：
文献类型：
--
作者：
Blakely PK;Hussain S;Carlin LE;Irani DN
基质细胞蛋白是一种酸性分泌蛋白，富含半胱氨酸（SPARC）和SPARC样1 (SPARCL1)，由星形胶质细胞产生并控制中枢神经系统的兴奋性突触发生。虽然SPARCL1在体外和体内发育中的神经系统中直接促进兴奋性突触的形成，但SPARC特异性地拮抗SPARCL1的突触形成作用。我们假设这些蛋白也有助于维持成年宿主中现有的兴奋性突触，并且脊髓局部炎症以动态调节运动突触的方式改变它们的产生，并影响小鼠实验性自身免疫性脑脊髓炎（EAE）期间瘫痪的严重程度。采用自发缓解型EAE模型，麻痹严重程度与脊髓灰质中突触蛋白的表达和与核周运动神经元直接接触的突触数量呈负相关。在缓解型和非缓解型EAE模型中，瘫痪严重程度也与腰椎脊髓组织中sparcl1:sparc转录本和sparcl1:sparc蛋白比例直接呈负相关。在体外，星形胶质细胞中SPARCL1和SPARC的产生均受T细胞源性细胞因子的调控，从而导致SPARCL1:SPARC表达比的动态调节。综上所述，这些数据支持一种模型，即促炎细胞因子抑制SPARCL1和/或增强SPARC在脊髓灰质中的表达，从而引起腰椎运动神经元的短暂或持续的突触收缩，从而调节EAE期间的后肢瘫痪。正在进行的研究寻求改变SPARCL1:SPARC表达比的方法，以支持突触的改造/维持，从而有助于调节炎症期间的神经功能缺陷。这可以确定新的星形胶质细胞靶向治疗疾病，如多发性硬化症。
The matricellular proteins, secreted protein acidic and rich in cysteine (SPARC) and SPARC-like 1 (SPARCL1), are produced by astrocytes and control excitatory synaptogenesis in the central nervous system. While SPARCL1 directly promotes excitatory synapse formation in vitro and in the developing nervous system in vivo, SPARC specifically antagonizes the synaptogenic actions of SPARCL1. We hypothesized these proteins also help maintain existing excitatory synapses in adult hosts, and that local inflammation in the spinal cord alters their production in a way that dynamically modulates motor synapses and impacts the severity of paralysis during experimental autoimmune encephalomyelitis (EAE) in mice. Using a spontaneously remitting EAE model, paralysis severity correlated inversely with both expression of synaptic proteins and the number of synapses in direct contact with the perikarya of motor neurons in spinal gray matter. In both remitting and non-remitting EAE models, paralysis severity also correlated inversely with sparcl1:sparc transcript and SPARCL1:SPARC protein ratios directly in lumbar spinal cord tissue. In vitro, astrocyte production of both SPARCL1 and SPARC was regulated by T cell-derived cytokines, causing dynamic modulation of the SPARCL1:SPARC expression ratio. Taken together, these data support a model whereby proinflammatory cytokines inhibit SPARCL1 and/or augment SPARC expression by astrocytes in spinal gray matter that, in turn, cause either transient or sustained synaptic retraction from lumbar spinal motor neurons thereby regulating hind limb paralysis during EAE. Ongoing studies seek ways to alter this SPARCL1:SPARC expression ratio in favor of synapse reformation/maintenance and thus help to modulate neurologic deficits during times of inflammation. This could identify new astrocyte-targeted therapies for diseases such as multiple sclerosis.