Neuroimmunology and Neuromuscular Disorders, Foundation IRCCS Neurological Institute Carlo Besta, Milan, Italy.
Neuropathol Appl Neurobiol. 2012 Jun;38(4):367-78. doi: 10.1111/j.1365-2990.2011.01212.x.
Recent studies propose the neurotrophin receptor p75NTR as a marker for muscle satellite cells and a key regulator of regenerative processes after injury. Here, we investigated the contribution of cellular compartments other than satellite cells and regenerating myofibres to p75NTR signal in diseased skeletal muscle.
We checked regulation of p75NTR expression in muscle biopsies from patients with inflammatory myopathies (polymyositis, dermatomyositis and inclusion body myositis), or Becker muscular dystrophy, and in nonmyopathic tissues. Quantitative PCR, immunohistochemistry, immunofluorescence or electron microscopy were used. RNA interference approaches were applied to myotubes to explore p75NTR function.
We found p75NTR transcript and protein upregulation in all inflammatory myopathies but not in dystrophic muscle, suggesting a role for inflammatory mediators in induction of p75NTR expression. In inflamed muscle p75NTR was localized on distinct cell types, including immune cells and mature myofibres. In vitro assays on human myotubes confirmed that inflammatory factors such as IL-1 could induce p75NTR. Finally, RNA interference experiments in differentiated cells showed that, in the absence of p75NTR, myotubes were more susceptible to apoptosis when exposed to inflammatory stimuli.
Our observations that p75NTR is upregulated on skeletal myofibres in inflammatory myopathies in vivo and promotes resistance to inflammatory mediators in vitro suggest that neurotrophin signalling through p75NTR may mediate a tissue-protective response to inflammation in skeletal myofibres.
最近的研究表明神经营养因子受体 p75NTR 可作为肌卫星细胞的标志物，也是损伤后再生过程的关键调节因子。在此，我们研究了除卫星细胞和再生肌纤维之外的细胞区室对病变骨骼肌中 p75NTR 信号的贡献。
我们检测了炎症性肌病（多发性肌炎、皮肌炎和包涵体肌炎）或 Becker 肌营养不良患者肌肉活检以及非肌病组织中 p75NTR 表达的调节情况。采用定量 PCR、免疫组织化学、免疫荧光或电子显微镜技术。应用 RNA 干扰方法研究了肌管中 p75NTR 的功能。
我们发现所有炎症性肌病中 p75NTR 转录本和蛋白均上调，但在营养不良性肌肉中没有上调，提示炎症介质在诱导 p75NTR 表达中起作用。在炎症肌肉中，p75NTR 定位于包括免疫细胞和成熟肌纤维在内的不同细胞类型上。体外研究证实，白细胞介素-1 等炎症因子可诱导 p75NTR 的表达。最后，在分化细胞中的 RNA 干扰实验表明，在不存在 p75NTR 的情况下，当暴露于炎症刺激时，肌管更容易发生凋亡。
我们的观察结果表明，p75NTR 在体内炎症性肌病的骨骼肌纤维上上调，并在体外促进对炎症介质的抗性，这表明通过 p75NTR 的神经营养因子信号可能介导骨骼肌纤维对炎症的组织保护反应。
