A pain-mediated neural signal induces relapse in murine autoimmune encephalomyelitis, a multiple sclerosis model.
A pain-mediated neural signal induces relapse in murine autoimmune encephalomyelitis, a multiple sclerosis model.
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DOI：
10.7554/elife.08733
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发表时间：
2015-08-11
期刊：
影响因子：
7.7
通讯作者：
Murakami M
中科院分区：
文献类型：
--
作者：
Arima Y;Kamimura D;Atsumi T;Harada M;Kawamoto T;Nishikawa N;Stofkova A;Ohki T;Higuchi K;Morimoto Y;Wieghofer P;Okada Y;Mori Y;Sakoda S;Saika S;Yoshioka Y;Komuro I;Yamashita T;Hirano T;Prinz M;Murakami M
虽然疼痛是各种疾病和障碍的常见症状，但其在疾病发病机制中的作用尚不清楚。在这里，我们使用小鼠实验性自身免疫性脑脊髓炎(EAE)，这是一种多发性硬化症(MS)的模型，显示疼痛导致EAE复发。机制分析表明，疼痛诱导激活了感觉-交感信号，随后由趋化因子介导的MHC II+CD11b+细胞积聚在EAE恢复小鼠的特定腹侧血管上，显示出抗原递呈活性。在这种积聚之后，各种免疫细胞，包括致病的CD4+T细胞，以依赖于内皮细胞局部趋化因子诱导剂的方式在脊髓内招募，导致EAE复发。我们的结果表明，疼痛介导的神经信号可以转化为特定血管上的炎症反应，从而诱导疾病复发，从而使该信号成为潜在的治疗靶点。DOI：http://dx.doi.org/10.7554/eLife.08733.001多发性硬化症(简称MS)是一种大脑和脊髓中神经细胞的绝缘层发炎和受损的疾病。根据受累神经的不同，这种疾病可能会引起一系列症状，从麻木和肌肉痉挛到视力障碍和慢性疼痛。许多其他疾病和障碍也以疼痛为症状，但疼痛本身是否直接导致疾病发展尚不清楚。大多数多发性硬化症患者最初会经历症状恶化的时期(称为复发)，然后是改善期。Arima、Kamimura等人的研究成果。研究了痛感本身是否会在多发性硬化症的小鼠模型中引发复发。实验表明，痛感可以通过所谓的“门户反射”在小鼠身上引发复发。这种反射描述了神经冲动导致信号分子释放的现象，这些信号分子导致附近血管的壁打开，并允许免疫细胞从血液流向中枢神经系统。这反过来又会刺激炎症的发展，从而导致中枢神经系统受影响部位的失衡。这些发现表明，疼痛本身会触发一种信号--通过神经冲动发送，然后释放信号分子--从而导致复发；并表明，干扰这一信号可能有助于治疗多发性硬化症，防止复发。从这项研究开始，重要的是确认人类是否存在门户反射，以及它是否与其他不涉及中枢神经系统的疾病有关。DOI：http://dx.doi.org/10.7554/eLife.08733.002
Although pain is a common symptom of various diseases and disorders, its contribution to disease pathogenesis is not well understood. Here we show using murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS), that pain induces EAE relapse. Mechanistic analysis showed that pain induction activates a sensory-sympathetic signal followed by a chemokine-mediated accumulation of MHC class II+CD11b+ cells that showed antigen-presentation activity at specific ventral vessels in the fifth lumbar cord of EAE-recovered mice. Following this accumulation, various immune cells including pathogenic CD4+ T cells recruited in the spinal cord in a manner dependent on a local chemokine inducer in endothelial cells, resulting in EAE relapse. Our results demonstrate that a pain-mediated neural signal can be transformed into an inflammation reaction at specific vessels to induce disease relapse, thus making this signal a potential therapeutic target. DOI: http://dx.doi.org/10.7554/eLife.08733.001 Multiple sclerosis (or MS for short) is a disease in which the insulating covers of nerve cells in the brain and spinal cord become inflamed and damaged. Depending on which nerves are affected, this disease can cause a wide range of symptoms, ranging from numbness and muscle spasms to visual disturbances and chronic pain. Many other diseases and disorders also have pain as a symptom, but it is not well understood if pain itself can directly contribute to the development of disease. Most people with MS will, initially, experience periods when their symptoms get worse (called ‘relapses’), which are then followed by periods of improvement. Arima, Kamimura et al. investigated whether the sensation of pain itself could trigger a relapse in a mouse model of MS. The experiments showed that a painful sensation could trigger a relapse in the mice via the so-called ‘gateway reflex’. This reflex describes the phenomenon whereby nerve impulses lead to the release of signaling molecules that cause the walls of nearby blood vessels to open and allow immune cells to move from the bloodstream to the central nervous system. This in turn stimulates the development of inflammation, which causes an imbalance in the affected sites of the central nervous system. These findings demonstrate that pain itself triggers a signal—sent via nerve impulses followed by the release of signaling molecules—that can lead to a relapse; and suggest that interfering with this signal could potentially help to treat to protect against relapses in MS. Following on from this work, it will be important to confirm if the gateway reflex exists in humans, and whether it is linked to other diseases that don't involve the central nervous system. DOI: http://dx.doi.org/10.7554/eLife.08733.002