Increased chemokine signaling in a model of HIV1-associated peripheral neuropathy.
Increased chemokine signaling in a model of HIV1-associated peripheral neuropathy.
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DOI：
10.1186/1744-8069-5-48
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发表时间：
2009-08-12
期刊：
影响因子：
3.3
通讯作者：
White FA
中科院分区：
文献类型：
--
作者：
Bhangoo SK;Ripsch MS;Buchanan DJ;Miller RJ;White FA
疼痛性远端感觉性多发性神经病（DSP）是HIV 1感染最常见的神经系统并发症。尽管病毒感染本身与DSP的发生率相关，但患者在开始核苷逆转录酶抑制剂（NRTI）治疗后更有可能出现症状。趋化因子单核细胞趋化蛋白-1（MCP 1/CCL 2）和基质衍生因子-1（SDF 1/CXCL 12）及其各自的受体CCR2和CXCR4已经涉及HIV 1相关的神经性疼痛机制，包括啮齿动物中的NRTI治疗。利用掺入病毒外壳蛋白、gp120和NRTI、2'3 '-双脱氧胞苷（ddC）的啮齿动物模型，我们检查了趋化因子受体信号传导通过CCR2和CXCR4潜在地影响所得慢性痛觉过敏行为的程度。我们观察到，在单侧给予gp120坐骨神经后，大鼠在gp120治疗同侧的后爪中产生了深刻的触觉痛觉过敏。行为变化也存在于损伤对侧的后爪中，尽管延迟且不太稳健。使用免疫组化研究，我们证明，MCP 1和CCR 2的上调，主要感觉神经元在腰神经节术后第14天（POD）。这些观察结果的功能性质，证实了使用钙成像在急性分离的腰背根神经节（DRG）从gp120损伤大鼠在POD 14。在POD 14用CCR 2受体拮抗剂处理后，gp120处理动物的触觉高伤害感受被逆转。在POD 14时，使一些组的动物经受gp120坐骨神经损伤与ddC注射的组合。这种损伤模式从POD 14 - 48产生明显的双侧触觉痛觉过敏。更重要的是，功能性MCP 1/CCR 2和SDF 1/CXCR 4信号传导存在于感觉神经元中。与单独的gp120治疗相反，与损伤加药物组合相关的高伤害性行为仅使用CXCR4拮抗剂AMD 3100有效逆转。这些研究表明，在gp120和NRTI组合后，CCR2和CXCR4信号传导系统的功能上调可能对相关DSP至关重要，并可能作为治疗该综合征的潜在治疗靶点。
Painful distal sensory polyneuropathy (DSP) is the most common neurological complication of HIV1 infection. Although infection with the virus itself is associated with an incidence of DSP, patients are more likely to become symptomatic following initiation of nucleoside reverse transcriptase inhibitor (NRTI) treatment. The chemokines monocyte chemoattractant protein-1 (MCP1/CCL2) and stromal derived factor-1 (SDF1/CXCL12) and their respective receptors, CCR2 and CXCR4, have been implicated in HIV1 related neuropathic pain mechanisms including NRTI treatment in rodents. Utilizing a rodent model that incorporates the viral coat protein, gp120, and the NRTI, 2'3'-dideoxycytidine (ddC), we examined the degree to which chemokine receptor signaling via CCR2 and CXCR4 potentially influences the resultant chronic hypernociceptive behavior. We observed that following unilateral gp120 sciatic nerve administration, rats developed profound tactile hypernociception in the hindpaw ipsilateral to gp120 treatment. Behavioral changes were also present in the hindpaw contralateral to the injury, albeit delayed and less robust. Using immunohistochemical studies, we demonstrated that MCP1 and CCR2 were upregulated by primary sensory neurons in lumbar ganglia by post-operative day (POD) 14. The functional nature of these observations was confirmed using calcium imaging in acutely dissociated lumbar dorsal root ganglion (DRG) derived from gp120 injured rats at POD 14. Tactile hypernociception in gp120 treated animals was reversed following treatment with a CCR2 receptor antagonist at POD 14. Some groups of animals were subjected to gp120 sciatic nerve injury in combination with an injection of ddC at POD 14. This injury paradigm produced pronounced bilateral tactile hypernociception from POD 14–48. More importantly, functional MCP1/CCR2 and SDF1/CXCR4 signaling was present in sensory neurons. In contrast to gp120 treatment alone, the hypernociceptive behavior associated with the injury plus drug combination was only effectively reversed using the CXCR4 antagonist AMD3100. These studies indicate that the functional upregulation of CCR2 and CXCR4 signaling systems following a combination of gp120 and an NRTI are likely to be of central importance to associated DSP and may serve as potential therapeutic targets for treatment of this syndrome.
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影响因子：
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