König Christian, Morch Eric, Eitner Annett, Möller Christian, Turnquist Brian, Schaible Hans-Georg, Ebersberger Andrea
Department of Physiology I/Neurophysiology, Jena University Hospital, Friedrich-Schiller-University of Jena, 07743 Jena, Germany, and.
Department of Math and Computer Science, Bethel University, St. Paul, Minnesota 55112.
J Neurosci. 2016 Sep 21;36(38):9782-91. doi: 10.1523/JNEUROSCI.4159-15.2016.
During peripheral inflammation, both spinal TNF-α and IL-6 are released within the spinal cord and support the generation of inflammation-evoked spinal hyperexcitability. However, whether spinal TNF-α and IL-6 act independently in parallel or in a functionally dependent manner has not been investigated. In extracellular recordings from mechanonociceptive deep dorsal horn neurons of normal rats in vivo, we found that spinal application of TNF-α increased spinal neuronal responses to mechanical stimulation of knee and ankle joints. This effect was significantly attenuated by either sgp130, which blocks IL-6 trans-signaling mediated by IL-6 and its soluble receptor IL-6R (sIL-6R); by an antibody to the IL-6 receptor; or by minocycline, which inhibits the microglia. IL-6 was localized in neurons of the spinal cord and, upon peripheral noxious stimulation in the presence of spinal TNF-α, IL-6 was released spinally. Furthermore, TNF-α recruited microglial cells to provide sIL-6R, which can form complexes with IL-6. Spinal application of IL-6 plus sIL-6R, but not of IL-6 alone, enhanced spinal hyperexcitability similar to TNF-α and the inhibition of TNF-α-induced hyperexcitability by minocycline was overcome by coadministration of sIL-6R, showing that sIL-6R is required. Neither minocycline nor the TNF-α-neutralizing compound etanercept inhibited the induction of hyperexcitability by IL-6 plus sIL-6R. Together, these data show that the induction of hyperexcitability of nociceptive deep dorsal horn neurons by TNF-α largely depends on the formation of IL-6/sIL-6R complexes that are downstream of TNF-α and requires the interactions of neurons and microglia orchestrated by TNF-α.
Both spinal TNF-α and IL-6 induce a state of spinal hyperexcitability. We present the novel finding that the full effect of TNF-α on the development of spinal hyperexcitability depends on IL-6 trans-signaling acting downstream of TNF-α. IL-6 trans-signaling requires the formation of complexes of IL-6 and soluble IL-6 receptor. Spinal TNF-α furthers the release of IL-6 from neurons in the spinal cord during peripheral noxious stimulation and recruits microglial cells to provide soluble IL-6 receptor, which can form complexes with IL-6. Therefore, a specific interaction between neurons and microglia is required for the full development of TNF-α-induced hyperexcitability of nociceptive deep horsal horn neurons.
在外周炎症期间，脊髓中的肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）都会释放，并支持炎症诱发的脊髓兴奋性过高的产生。然而，脊髓TNF-α和IL-6是独立并行起作用还是功能依赖方式起作用尚未得到研究。在正常大鼠体内机械性伤害感受性背角深层神经元的细胞外记录中，我们发现脊髓应用TNF-α会增加脊髓神经元对膝关节和踝关节机械刺激的反应。sgp130（可阻断由IL-6及其可溶性受体IL-6R介导的IL-6转信号传导）、抗IL-6受体抗体或抑制小胶质细胞的米诺环素，均可显著减弱这种效应。IL-6定位于脊髓神经元中，在外周有害刺激且存在脊髓TNF-α的情况下，IL-6会在脊髓中释放。此外，TNF-α募集小胶质细胞以提供sIL-6R，其可与IL-6形成复合物。脊髓应用IL-6加sIL-6R，但单独应用IL-6则不会，可增强脊髓兴奋性过高，类似于TNF-α，并且米诺环素对TNF-α诱导的兴奋性过高的抑制作用可通过共同给予sIL-6R而被克服，表明sIL-6R是必需的。米诺环素和TNF-α中和化合物依那西普均未抑制IL-6加sIL-6R诱导的兴奋性过高。总之，这些数据表明，TNF-α诱导伤害性背角深层神经元兴奋性过高在很大程度上取决于TNF-α下游IL-6/sIL-6R复合物的形成，并且需要TNF-α协调神经元和小胶质细胞的相互作用。
脊髓TNF-α和IL-6均会诱导脊髓兴奋性过高状态。我们提出了一项新发现，即TNF-α对脊髓兴奋性过高发展的全部作用取决于TNF-α下游的IL-6转信号传导。IL-6转信号传导需要IL-6和可溶性IL-6受体形成复合物。在外周有害刺激期间，脊髓TNF-α会促进脊髓神经元释放IL-6，并募集小胶质细胞以提供可溶性IL-6受体，其可与IL-6形成复合物。因此，TNF-α诱导的伤害性背角深层神经元兴奋性过高的充分发展需要神经元和小胶质细胞之间的特定相互作用。
