Relationship Between the Chemokine Receptor CCR5 and Microglia in Neurological Disorders: Consequences of Targeting CCR5 on Neuroinflammation, Neuronal Death and Regeneration in a Model of Epilepsy
Relationship Between the Chemokine Receptor CCR5 and Microglia in Neurological Disorders: Consequences of Targeting CCR5 on Neuroinflammation, Neuronal Death and Regeneration in a Model of Epilepsy
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DOI：
10.2174/18715273113126660173
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发表时间：
2013-09-01
影响因子：
3
通讯作者：
Strayer, David S.
中科院分区：
文献类型：
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作者：
Louboutin, Jean-Pierre;Strayer, David S.
趋化因子可能在神经炎症和其他神经病理过程（如癫痫）中白细胞穿过血脑屏障（BBB）的迁移中发挥作用。CC趋化因子受体5（CCR 5）是CC-趋化因子受体家族的成员，其结合多种趋化因子，包括CCL 3（巨噬细胞炎性蛋白-1 α，MIP-1 α）、CCL 4（巨噬细胞炎性蛋白-1 β，MIP-1 β）和CCL 5（RANTES）。本文综述了CCR 5与小胶质细胞在不同神经系统疾病和CNS损伤模型中的关系。CCR 5表达在不同的神经系统疾病中上调，其中它通常在小胶质细胞中免疫定位。在人类小胶质细胞中，趋化因子激活CCR 5与Ca（2+）增加的多步级联反应偶联。由于[Ca（2+）]（i）的变化影响趋化性、分泌和基因表达，因此该途径的药理学调节可能改变CNS中的炎症和退行性过程。因此，通过使用CCR 5拮抗剂靶向CCR 5可以减弱不同神经障碍模型中神经炎症的关键方面。为了说明CCR 5和小胶质细胞在中枢神经系统中的相互作用，我们使用了兴奋性毒性模型，并证明了CCR 5密切参与神经元损伤和炎症伴随红藻氨酸（KA）诱导的神经毒性。CCR 5参与由兴奋毒素KA引起的神经元损伤，将炎性细胞带到KA诱导的CNS损伤的部位，限定KA暴露后组织损失的程度并限制修复反应。我们使用了SV 40衍生的载体，该载体携带靶向CCR 5的干扰RNA（RNAi）。直接递送至骨髓，该载体降低循环细胞中的CCR 5表达。如此处理的动物显示出CCR 5及其配体（MIP-1 α和RANTES）在CNS（包括脑血管系统）中的表达大大降低，BBB渗漏减少，显示出更大的KA刺激的神经发生和骨髓来源的细胞向脑迁移成为神经元的增加。因此，CCR 5的治疗靶向可能允许控制潜在的损伤性神经炎症反应，包括减少小胶质细胞活化和增殖，并促进脑损伤诱导的和潜在的其他形式的CNS损伤的神经源性修复。
Chemokines may play a role in leukocyte migration across the blood-brain barrier (BBB) during neuroinflammation and other neuropathological processes, such as epilepsy. The CC chemokine receptor 5 (CCR5) is a member of CC-chemokine receptor family that binds several chemokines, including CCL3 (macrophage inflammatory protein-1alpha, MIP-1alpha), CCL4 (macrophage inflammatory protein-1beta, MIP-1beta) and CCL5 (RANTES). The current review examines the relationship between CCR5 and the microglia in different neurological disorders and models of CNS injury. CCR5 expression is upregulated in different neurological diseases, where it is often immunolocalized in microglial cells. A multistep cascade couples CCR5 activation by chemokines to Ca(2+) increases in human microglia. Because changes in [Ca(2+)] (i) affect chemotaxis, secretion, and gene expression, pharmacologic modulation of this pathway may alter inflammatory and degenerative processes in the CNS. Consequently, targeting CCR5 by using CCR5 antagonists may attenuate critical aspects of neuroinflammation in different models of neurological disorders. To illustrate the interaction between CCR5 and microglia in the CNS, we used a model of excitotoxicity, and demonstrate the intimate involvement of CCR5 in neuron injury and inflammation attendant to kainic acid (KA)-induced neurotoxicity. CCR5 participates in neuronal injury caused by the excitotoxin, KA, brings inflammatory cells to the sites of KA-induced CNS injury, defines the extent of tissue loss after KA exposure and limits reparative responses. We used a SV40-derived vector carrying an interfering RNA (RNAi) that targets CCR5. Delivered directly to the bone marrow, this vector decreased CCR5 expression in circulating cells. Animals so treated showed greatly reduced expression of CCR5 and its ligands (MIP-1alpha and RANTES) in the CNS, including in the brain vasculature, decreased BBB leakage, demonstrated greater KA-stimulated neurogenesis and increased migration of bone marrow-derived cells to the brain to become neurons. Thus, therapeutic targeting of CCR5 may allow control of potentially injurious neuroinflammatory responses, including decrease in microglial cells activation and proliferation, and facilitate neurogenic repair in seizure-induced and, potentially, other forms of CNS injury.