Laboratories of Neuroimmunology, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
Department of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
Proc Natl Acad Sci U S A. 2020 Mar 10;117(10):5463-5471. doi: 10.1073/pnas.1913444117. Epub 2020 Feb 20.
Chronic pain is a major clinical problem of which the mechanisms are incompletely understood. Here, we describe the concept that PI16, a protein of unknown function mainly produced by fibroblasts, controls neuropathic pain. The spared nerve injury (SNI) model of neuropathic pain increases PI16 protein levels in fibroblasts in dorsal root ganglia (DRG) meninges and in the epi/perineurium of the sciatic nerve. We did not detect PI16 expression in neurons or glia in spinal cord, DRG, and nerve. Mice deficient in PI16 are protected against neuropathic pain. In vitro, PI16 promotes transendothelial leukocyte migration. In vivo, mice show reduced endothelial barrier permeability, lower leukocyte infiltration and reduced activation of the endothelial barrier regulator MLCK, and reduced phosphorylation of its substrate MLC2 in response to SNI. In summary, our findings support a model in which PI16 promotes neuropathic pain by mediating a cross-talk between fibroblasts and the endothelial barrier leading to barrier opening, cellular influx, and increased pain. Its key role in neuropathic pain and its limited cellular and tissue distribution makes PI16 an attractive target for pain management.
慢性疼痛是一个主要的临床问题，其机制尚未完全了解。在这里，我们描述了一个概念，即 PI16，一种主要由成纤维细胞产生的未知功能的蛋白质，控制着神经性疼痛。神经病理性疼痛的 spared nerve injury (SNI) 模型增加了背根神经节 (DRG) 脑膜和成坐骨神经的外膜/神经周的 PI16 蛋白水平。我们没有在脊髓、DRG 和神经中检测到神经元或神经胶质中的 PI16 表达。缺乏 PI16 的小鼠对神经病理性疼痛有保护作用。在体外，PI16 促进了跨内皮白细胞迁移。在体内，PI16 减少了内皮屏障通透性，减少了白细胞浸润和内皮屏障调节剂 MLCK 的激活，以及对 SNI 反应的其底物 MLC2 的磷酸化。总之，我们的研究结果支持这样一种模型，即 PI16 通过介导成纤维细胞和内皮屏障之间的串扰来促进神经病理性疼痛，导致屏障开放、细胞内流和疼痛增加。PI16 在神经病理性疼痛中的关键作用及其有限的细胞和组织分布使其成为疼痛管理的一个有吸引力的靶点。
