Sensitization of knee-innervating sensory neurons by tumor necrosis factor-α-activated fibroblast-like synoviocytes: an in vitro, coculture model of inflammatory pain
Sensitization of knee-innervating sensory neurons by tumor necrosis factor-α-activated fibroblast-like synoviocytes: an in vitro, coculture model of inflammatory pain
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DOI：
10.1097/j.pain.0000000000001890
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发表时间：
2020-09-01
期刊：
影响因子：
7.4
通讯作者：
Smith, Ewan St John
中科院分区：
文献类型：
--
作者：
Chakrabarti, Sampurna;Hore, Zoe;Smith, Ewan St John
疼痛是关节炎全球负担的主要因素，外周致敏是关节炎相关疼痛的主要原因。在膝关节内，背根神经节神经元（膝神经元）的远端与成纤维细胞样滑膜细胞（FLS）及其分泌的炎症介质相互作用，这被认为是促进外周致敏。相应地，RNA测序已经证明在源自关节炎患者的FLS中存在可检测水平的促炎基因。该研究证实，用肿瘤坏死因子（TNF-α）刺激导致小鼠和人FLS（源自骨关节炎和类风湿性关节炎患者）中促炎基因的表达，以及小鼠TNF-α刺激的FLS（TNF-FLS）的细胞因子分泌增加。逆行标记的膝关节神经元与TNF-FLS共培养，或来自TNF-FLS的上清液的电生理记录，揭示了去极化的静息膜电位，增加自发动作电位放电，增强TRPV 1功能，所有这些都与FLS在介导关节炎疼痛感觉神经敏化中的作用一致。因此，本研究的数据表明，由TNF-α激活的FLS能够促进神经元致敏，结果突出了非神经元和神经元细胞对关节炎疼痛发展的重要性。
Pain is a principal contributor to the global burden of arthritis with peripheral sensitization being a major cause of arthritis-related pain. Within the knee joint, distal endings of dorsal root ganglion neurons (knee neurons) interact with fibroblast-like synoviocytes (FLS) and the inflammatory mediators they secrete, which are thought to promote peripheral sensitization. Correspondingly, RNA sequencing has demonstrated detectable levels of proinflammatory genes in FLS derived from arthritis patients. This study confirms that stimulation with tumor necrosis factor (TNF-alpha) results in expression of proinflammatory genes in mouse and human FLS (derived from osteoarthritis and rheumatoid arthritis patients), as well as increased secretion of cytokines from mouse TNF-alpha-stimulated FLS (TNF-FLS). Electrophysiological recordings from retrograde labelled knee neurons cocultured with TNF-FLS, or supernatant derived from TNF-FLS, revealed a depolarized resting membrane potential, increased spontaneous action potential firing, and enhanced TRPV1 function, all consistent with a role for FLS in mediating the sensitization of pain-sensing nerves in arthritis. Therefore, data from this study demonstrate the ability of FLS activated by TNF-alpha to promote neuronal sensitization, results that highlight the importance of both nonneuronal and neuronal cells to the development of pain in arthritis.