Spinal IL-36γ/IL-36R participates in the maintenance of chronic inflammatory pain through astroglial JNK pathway
Spinal IL-36γ/IL-36R participates in the maintenance of chronic inflammatory pain through astroglial JNK pathway
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脊髓IL-36γ/IL-36R通过星形胶质细胞JNK通路参与慢性炎性疼痛的维持
DOI：
10.1002/glia.23552
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发表时间：
2019-03-01
期刊：
影响因子：
6.2
通讯作者：
Zhou, Junmei
中科院分区：
文献类型：
--
作者：
Li, Qian;Liu, Shenbin;Zhou, Junmei
新的证据表明脊髓神经炎症有助于维持慢性炎性疼痛。 IL-36作为白细胞介素(IL)-1超家族细胞因子的新成员，在炎症反应中发挥着重要作用。本研究旨在探讨脊髓 IL-36 和 IL-36 受体 (IL-36R) 信号在慢性炎症疼痛病理学中的作用。足底注射完全弗氏佐剂 (CFA) 的小鼠脊髓中，IL-36 γ 和 IL-36R 持续上调，但 IL-36 α 和 IL-36 β 没有持续上调。鞘内注射 IL-36R 拮抗剂 (IL-36Ra) 和 IL-36 γ siRNA 可显着减轻 CFA 诱导的慢性炎症疼痛行为。此外，CFA诱导的IL-36γ表达主要在脊髓神经元中观察到，而IL-36R主要在脊髓星形胶质细胞中表达。此外，鞘内注射 IL-36 γ 足以诱导首次实验小鼠的疼痛过敏和星形胶质细胞活化，并且可以通过阻断 c-Jun N 末端激酶 (JNK) 磷酸化来抑制这些作用。体外实验还表明，IL-36γ可以诱导星形胶质细胞JNK激活和炎性细胞因子释放，这是由IL-36R介导的。最后，以 pJNK 依赖性方式鞘内注射 IL-36 γ 激活的星形胶质细胞诱导首次实验小鼠的机械异常性疼痛和热痛觉过敏。总的来说，这些发现表明，脊髓中神经元/星形胶质细胞的相互作用，神经元产生的 IL-36 γ 通过 IL-36R 介导的 JNK 途径激活星形胶质细胞，对于维持慢性炎性疼痛至关重要。因此，IL-36γ/IL-36R介导的星形胶质细胞信号传导可能是慢性炎性疼痛的合适治疗靶点。
Emerging evidence indicates that spinal neuroinflammation contributes to the maintenance of chronic inflammatory pain. IL-36, as a novel member of the interleukin (IL)-1 super-family cytokines, plays an important role in inflammatory responses. The present study aimed to investigate the role of spinal IL-36 and IL-36 receptor (IL-36R) signaling in the pathology of chronic inflammatory pain. IL-36 gamma and IL-36R, but not IL-36 alpha and IL-36 beta, were persistently upregulated in the spinal cord of mice with intraplantar injections of complete Freund's adjuvant (CFA). Intrathecal administration of both IL-36R antagonist (IL-36Ra) and IL-36 gamma siRNA significantly attenuated CFA-induced chronic inflammatory pain behaviors. Furthermore, CFA-induced IL-36 gamma expression was mainly observed in spinal neurons whereas IL-36R was primarily expressed in spinal astrocytes. Additionally, the intrathecal injection of IL-36 gamma was sufficient to induce pain hypersensitivity and astrocyte activation in naive mice, and these effects could be inhibited by blocking c-Jun N-terminal kinase (JNK) phosphorylation. In vitro experiments also demonstrated that the IL-36 gamma could induce astrocytic JNK activation and inflammatory cytokines release, which was mediated by IL-36R. Finally, intrathecal injection of IL-36 gamma-activated astrocytes in a pJNK-dependent manner induced mechanical allodynia and thermal hyperalgesia in naive mice. Collectively, these findings reveal that the neuronal/astrocytic interaction in the spinal cord by which neuronally produced IL-36 gamma activates astrocytes via IL-36R-mediated JNK pathway is crucial for the maintenance of chronic inflammatory pain. Thus, IL-36 gamma/IL-36R-mediated astrocyte signaling may be a suitable therapeutic target for chronic inflammatory pain.