An Autocrine Neuronal Interleukin-6 Loop Mediates Chloride Accumulation and NKCC1 Phosphorylation in Axotomized Sensory Neurons
An Autocrine Neuronal Interleukin-6 Loop Mediates Chloride Accumulation and NKCC1 Phosphorylation in Axotomized Sensory Neurons
复制标题
DOI：
10.1523/jneurosci.3382-11.2011
复制
发表时间：
2011-09
期刊：
影响因子：
--
通讯作者：
S. Pieraut;O. Lucas;Sina Sangari;Chamroeun Sar;Mathieu Boudes;C. Bouffi;D. Noel;F. Scamps
中科院分区：
文献类型：
--
作者：
S. Pieraut;O. Lucas;Sina Sangari;Chamroeun Sar;Mathieu Boudes;C. Bouffi;D. Noel;F. Scamps
阳离子-氯离子共转运体NKCC1通过设定细胞内氯浓度的值，在中枢和外周神经系统中发挥着重要的作用。周围神经损伤后，NKCC1磷酸化诱导的氯离子积聚有助于感觉神经元轴突的再生。然而，调控NKCC1活性的分子和信号通路仍有待确定。共转运蛋白活性的功能分析显示，用抗鼠IL-6抗体或在IL-6−/−小鼠中抑制内源性产生的细胞因子IL-6，可以防止氯离子在轴突切断的神经元亚群中积聚。神经损伤上调小鼠腰背根神经节有髓鞘TrkB阳性感觉神经元IL-6受体的转录和蛋白水平。磷酸化NKCC1主要在表达IL-6受体的感觉神经元中表达，而在IL-6−/−背根神经节中不表达。使用IL-6受体阻断功能抗体或可溶性IL-6受体，结合Janus激酶的药物抑制，证实了神经元IL-6信号在氯离子积聚和轴突生长中的作用。因此，在病理生理条件下，IL-6受体的细胞特异性表达是一种细胞反应，通过神经元NKCC1的磷酸化和氯的积累，IL-6有助于神经再生。
The cation-chloride cotransporter NKCC1 plays a fundamental role in the central and peripheral nervous systems by setting the value of intracellular chloride concentration. Following peripheral nerve injury, NKCC1 phosphorylation-induced chloride accumulation contributes to neurite regrowth of sensory neurons. However, the molecules and signaling pathways that regulate NKCC1 activity remain to be identified. Functional analysis of cotransporter activity revealed that inhibition of endogenously produced cytokine interleukin-6 (IL-6), with anti-mouse IL-6 antibody or in IL-6−/− mice, prevented chloride accumulation in a subset of axotomized neurons. Nerve injury upregulated the transcript and protein levels of IL-6 receptor in myelinated, TrkB-positive sensory neurons of murine lumbar dorsal root ganglia. Expression of phospho-NKCC1 was observed mainly in sensory neurons expressing IL-6 receptor and was absent from IL-6−/− dorsal root ganglia. The use of IL-6 receptor blocking-function antibody or soluble IL-6 receptor, together with pharmacological inhibition of Janus kinase, confirmed the role of neuronal IL-6 signaling in chloride accumulation and neurite growth of a subset of axotomized sensory neurons. Cell-specific expression of interleukin-6 receptor under pathophysiological conditions is therefore a cellular response by which IL-6 contributes to nerve regeneration through neuronal NKCC1 phosphorylation and chloride accumulation.