Allergic Inflammation Leads to Neuropathic Pain via Glial Cell Activation
Allergic Inflammation Leads to Neuropathic Pain via Glial Cell Activation
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DOI：
10.1523/jneurosci.1981-16.2016
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发表时间：
2016-11
期刊：
影响因子：
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通讯作者：
R. Yamasaki;T. Fujii;B. Wang;K. Masaki;M. Kido;Mari Yoshida;T. Matsushita;J. Kira
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文献类型：
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作者：
R. Yamasaki;T. Fujii;B. Wang;K. Masaki;M. Kido;Mari Yoshida;T. Matsushita;J. Kira
过敏性和特应性疾病在过去几十年中有所增加，并与神经精神疾病有关，如自闭症谱系障碍和哮喘性肌萎缩。特应性疾病患者可发生以神经病理性疼痛为表现的脊髓炎；然而，过敏性炎症和神经病理性疼痛之间的关系及其潜在机制仍有待确定。我们研究了过敏性炎症是否会影响脊柱伤害性感受系统。我们发现，有哮喘、特应性皮炎或特应性素质的小鼠脊髓中的小胶质细胞和星形胶质细胞比没有特应性的小鼠广泛且显著地更活跃，并表现出触觉过敏。对分离的小胶质细胞的微阵列分析显示，在特应性小鼠中，M1巨噬细胞标志物上调，M2标志物下调，表现为异常表型。在细胞表面蛋白基因中，内皮素受体B型(EDNRB)表达上调最多。免疫组织化学分析显示，EDNRB在小胶质细胞和星形胶质细胞中的表达增强，而EDNRB配体内皮素-1在血清、肺和表皮中的表达增加。脊髓中未见Ednra的表达。FBJ小鼠骨肉瘤病毒同源基因B在哮喘小鼠的背角神经元中的表达显著高于非特应性小鼠。EDNRB拮抗剂BQ788可消除神经胶质细胞和神经的激活以及痛觉异常。我们发现有脊髓炎和神经病理性疼痛的特应性患者血清内皮素-1升高，在尸检病例中，随着EDNRB上调，脊髓小胶质细胞和星形胶质细胞激活。这些结果表明，变态反应性炎症通过EDNRB途径诱导弥漫性胶质细胞激活，影响伤害性感受系统。意义陈述在过去的几十年里，过敏性疾病的患病率显著增加。过敏性疾病与神经精神疾病有关；然而，过敏性炎症和中枢神经系统并发症之间的关系尚不清楚。一种特殊的脊髓炎表现为持续的神经病理性疼痛，已有报道出现在过敏性疾病患者中。我们研究了特应性如何对伤害性感觉系统产生实质性影响。我们发现，过敏性疾病小鼠有严重的痛觉异常，星形胶质细胞和小胶质细胞激活，脊髓内内皮素-1(ET-1)受体B型(EDNRB)明显上调。选择性EDNRB拮抗剂可防止痛觉过敏和神经胶质细胞的激活。我们的发现提示了一种新的机制，即特应性反应通过ET-1/EDNRB途径诱导神经胶质细胞激活和神经病理性疼痛。
Allergic and atopic disorders have increased over the past few decades and have been associated with neuropsychiatric conditions, such as autism spectrum disorder and asthmatic amyotrophy. Myelitis presenting with neuropathic pain can occur in patients with atopic disorder; however, the relationship between allergic inflammation and neuropathic pain, and the underlying mechanism, remains to be established. We studied whether allergic inflammation affects the spinal nociceptive system. We found that mice with asthma, atopic dermatitis, or atopic diathesis had widespread and significantly more activated microglia and astroglia in the spinal cord than those without atopy, and displayed tactile allodynia. Microarray analysis of isolated microglia revealed a dysregulated phenotype showing upregulation of M1 macrophage markers and downregulation of M2 markers in atopic mice. Among the cell surface protein genes, endothelin receptor type B (EDNRB) was most upregulated. Immunohistochemical analysis revealed that EDNRB expression was enhanced in microglia and astroglia, whereas endothelin-1, an EDNRB ligand, was increased in serum, lungs, and epidermis of atopic mice. No EDNRA expression was found in the spinal cord. Expression of FBJ murine osteosarcoma viral oncogene homolog B was significantly higher in the dorsal horn neurons of asthma mice than nonatopic mice. The EDNRB antagonist BQ788 abolished glial and neural activation and allodynia. We found increased serum endothelin-1 in atopic patients with myelitis and neuropathic pain, and activation of spinal microglia and astroglia with EDNRB upregulation in an autopsied case. These results suggest that allergic inflammation induces diffuse glial activation, influencing the nociceptive system via the EDNRB pathway. SIGNIFICANCE STATEMENT The prevalence of allergic disorders has markedly increased over the past few decades. Allergic disorders are associated with neuropsychiatric conditions; however, the relationship between allergic inflammation and CNS complications is unknown. A peculiar myelitis presenting with persistent neuropathic pain has been reported in patients with allergic disorders. We studied how atopy exerts substantial influence on the nociceptive system. We found that mice with allergic disorders had severe allodynia with activated astroglia and microglia, and showed marked upregulation of endothelin-1 (ET-1) receptor type B (EDNRB) in the spinal cord. A selective EDNRB antagonist prevented allodynia and glial activation. Our findings suggest a novel mechanism whereby atopy induces glial activation and neuropathic pain via an ET-1/EDNRB pathway.