Role of the Fractalkine Receptor in CNS Autoimmune Inflammation: New Approach Utilizing a Mouse Model Expressing the Human CX3CR1(I249/M280) Variant.
Role of the Fractalkine Receptor in CNS Autoimmune Inflammation: New Approach Utilizing a Mouse Model Expressing the Human CX3CR1(I249/M280) Variant.
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Fractalkine受体在CNS自身免疫炎症中的作用：利用表达人CX 3CR 1（I249/M280）变体的小鼠模型的新方法。
DOI：
10.3389/fncel.2018.00365
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发表时间：
2018
影响因子：
5.3
通讯作者：
Cardona AE
中科院分区：
文献类型：
--
作者：
Cardona SM;Kim SV;Church KA;Torres VO;Cleary IA;Mendiola AS;Saville SP;Watowich SS;Parker-Thornburg J;Soto-Ospina A;Araque P;Ransohoff RM;Cardona AE
多发性硬化症 (MS) 是一种中枢神经系统 (CNS) 炎症性脱髓鞘疾病，是年轻人非创伤性神经功能障碍的主要原因。免疫介导的髓磷脂和少突胶质细胞破坏被认为是多发性硬化症的主要病理，但进行性轴突损失是神经功能障碍的主要原因。为了了解中枢神经系统炎症期间小胶质细胞的功能，我们的实验室重点研究 fractalkine/CX3CR1 信号传导作为各种神经退行性变模型中小胶质细胞神经毒性的调节剂。 Fractalkine (FKN) 是一种跨膜趋化因子，由神经元在 CNS 中表达，并通过小胶质细胞中存在的独特受体 CX3CR1 发出信号。在实验性自身免疫性脑脊髓炎 (EAE) 过程中，CX3CR1 缺乏会导致病情恶化，表现为严重炎症和神经元损失。大约 20% 的人群中存在 CX3CR1 人类多态性 I249/M280，其对 FKN 的粘附力降低，从而导致信号传导缺陷，其在 MS 期间小胶质细胞功能和对神经元的影响中的作用仍未解决。本研究的目的是评估 EAE 期间通过 hCX3CR1I249/M280 的较弱信号传导的影响。我们假设，由于 CX3CR1 信号传导受损，小胶质细胞反应失调会增强神经元/轴突损伤。我们生成了一个动物模型，替换 hCX3CR1I249/M280 变体的小鼠 CX3CR1 基因座。在 EAE 诱导后，这些小鼠表现出与严重炎症和神经元损失相关的加剧的 EAE。我们还观察到，与野生型小鼠相比，CX3CR1 信号异常的小鼠在 EAE 期间无法产生 FKN 和睫状神经营养因子。我们的结果验证了 hCX3CR1I249/M280 变体的功能缺陷，并为扩大对神经炎症期间小胶质细胞功能障碍的理解奠定了基础。
Multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS) is the leading cause of non-traumatic neurological disability in young adults. Immune mediated destruction of myelin and oligodendrocytes is considered the primary pathology of MS, but progressive axonal loss is the major cause of neurological disability. In an effort to understand microglia function during CNS inflammation, our laboratory focuses on the fractalkine/CX3CR1 signaling as a regulator of microglia neurotoxicity in various models of neurodegeneration. Fractalkine (FKN) is a transmembrane chemokine expressed in the CNS by neurons and signals through its unique receptor CX3CR1 present in microglia. During experimental autoimmune encephalomyelitis (EAE), CX3CR1 deficiency confers exacerbated disease defined by severe inflammation and neuronal loss. The CX3CR1 human polymorphism I249/M280 present in ∼20% of the population exhibits reduced adhesion for FKN conferring defective signaling whose role in microglia function and influence on neurons during MS remains unsolved. The aim of this study is to assess the effect of weaker signaling through hCX3CR1I249/M280 during EAE. We hypothesize that dysregulated microglial responses due to impaired CX3CR1 signaling enhance neuronal/axonal damage. We generated an animal model replacing the mouse CX3CR1 locus for the hCX3CR1I249/M280 variant. Upon EAE induction, these mice exhibited exacerbated EAE correlating with severe inflammation and neuronal loss. We also observed that mice with aberrant CX3CR1 signaling are unable to produce FKN and ciliary neurotrophic factor during EAE in contrast to wild type mice. Our results provide validation of defective function of the hCX3CR1I249/M280 variant and the foundation to broaden the understanding of microglia dysfunction during neuroinflammation.
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影响因子：
14.8
作者：
Kelley LA;Mezulis S;Yates CM;Wass MN;Sternberg MJ
通讯作者：
Sternberg MJ
影响因子：
16.2
作者：
Bhaskar, Kiran;Konerth, Megan;Kokiko-Cochran, Olga N.;Cardona, Astrid;Ransohoff, Richard M.;Lamb, Bruce T.
通讯作者：
Lamb, Bruce T.
影响因子：
5.3
作者：
Jung, S;Aliberti, J;Littman, DR
通讯作者：
Littman, DR
影响因子：
8.6
作者：
Blauth, Kevin;Zhang, Xin;Markovic-Plese, Silva
通讯作者：
Markovic-Plese, Silva
DOI：
10.1523/jneurosci.3174-09.2010
发表时间：
2010-02-24
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Cao Q;He Q;Wang Y;Cheng X;Howard RM;Zhang Y;DeVries WH;Shields CB;Magnuson DS;Xu XM;Kim DH;Whittemore SR
通讯作者：
Whittemore SR