Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL 33136, United States The Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, United States The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, United States.
Pain. 2010 Mar;148(3):509-518. doi: 10.1016/j.pain.2010.01.001. Epub 2010 Jan 22.
The transcription factor nuclear factor kappa B (NF-kappaB) is a key regulator of inflammatory processes in reactive glial cells. We utilized a transgenic mouse model (GFAP-IkappaBalpha-dn) where the classical NF-kappaB pathway is inactivated by overexpression of a dominant negative (dn) form of the inhibitor of kappa B (IkappaBalpha) in glial fibrillary acidic protein (GFAP)-expressing cells, which include astrocytes, Schwann cells, and satellite cells of the dorsal root ganglion (DRG) and sought to determine whether glial NF-kappaB inhibition leads to a reduction in pain behavior and inflammation following chronic constriction injury (CCI) of the sciatic nerve. As expected, following CCI nuclear translocation, and hence activation, of NF-kappaB was detected only in the sciatic nerve of wild type (WT) mice, and not in GFAP-IkappaBalpha-dn mice, while upregulation of GFAP was observed in the sciatic nerve and DRGs of both WT and GFAP-IkappaBalpha-dn mice, indicative of glial activation. Following CCI, mechanical and thermal hyperalgesia were reduced in GFAP-IkappaBalpha-dn mice compared to those in WT, as well as gene and protein expression of CCL2, CCR2 and CXCL10 in the sciatic nerve. Additionally, gene expression of TNF, CCL2, and CCR2 was reduced in the DRGs of transgenic mice compared to those of WT after CCI. We can therefore conclude that transgenic inhibition of NF-kappaB in GFAP-expressing glial cells attenuated pain and inflammation after peripheral nerve injury. These findings suggest that targeting the inflammatory response in Schwann cells and satellite cells may be important in treating neuropathic pain.
转录因子核因子 kappa B（NF-κB）是反应性神经胶质细胞中炎症过程的关键调节因子。我们利用一种转基因小鼠模型（GFAP-IκBα-dn），其中经典 NF-κB 途径通过在 GFAP 表达细胞中过表达抑制物 kappa B（IκBα）的显性负（dn）形式而失活，GFAP 表达细胞包括星形胶质细胞、施万细胞和背根神经节（DRG）的卫星细胞，我们试图确定胶质细胞 NF-κB 抑制是否会导致坐骨神经慢性缩窄性损伤（CCI）后疼痛行为和炎症减少。正如预期的那样，CCI 后，只有在野生型（WT）小鼠的坐骨神经中检测到 NF-κB 的核易位，从而激活，而在 GFAP-IκBα-dn 小鼠中未检测到，而在 WT 和 GFAP-IκBα-dn 小鼠的坐骨神经和 DRG 中观察到 GFAP 的上调，表明胶质细胞激活。CCI 后，GFAP-IκBα-dn 小鼠的机械和热痛觉过敏较 WT 小鼠减轻，坐骨神经中 CCL2、CCR2 和 CXCL10 的基因和蛋白表达也减少。此外，CCI 后，转基因小鼠的 DRG 中 TNF、CCL2 和 CCR2 的基因表达较 WT 小鼠减少。因此，我们可以得出结论，GFAP 表达胶质细胞中 NF-κB 的转基因抑制减轻了周围神经损伤后的疼痛和炎症。这些发现表明，针对施万细胞和卫星细胞中的炎症反应可能对治疗神经病理性疼痛很重要。
