Spinal IL‐36γ/IL‐36R participates in the maintenance of chronic inflammatory pain through astroglial JNK pathway. Issue 3 (21st December 2018)

• Record Type: Journal Article
• Authors: Li, Qian; Liu, Shenbin; Li, Lingling; Ji, Xiaoli; Wang, Min; Zhou, Junmei
• Is Part Of: Glia. Volume 67:Issue 3(2019)
• Page Start: 438
• Page End: 451
• Publication Date: 2018-12-21
• Subjects: astrocyte -- IL‐36 -- IL‐36 receptor -- inflammatory pain -- mice; Neuroglia -- Periodicals; Neurology -- Periodicals; 611.0188
• DOI: 10.1002/glia.23552
• Languages: English
• ISSNs: 0894-1491

Abstract

Abstract: 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‐36γ and IL‐36R, but not IL‐36α and IL‐36β, 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‐36γ siRNA significantly attenuated CFA‐induced chronic inflammatory pain behaviors. Furthermore, CFA‐induced IL‐36γ expression was mainly observed in spinal neurons whereas IL‐36R was primarily expressed in spinal astrocytes. Additionally, the intrathecal injection of IL‐36γ 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‐36γ could induce astrocytic JNK activation and inflammatory cytokines release, which was mediated by IL‐36R. Finally, intrathecal injection of IL‐36γ‐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‐36γ activates astrocytes via IL‐36R‐mediated JNK pathway is crucial for the maintenance of chronic inflammatory pain. Thus, IL‐36γ/IL‐36R‐mediated astrocyte signaling may be a suitable therapeutic target for chronic inflammatory pain. Main Points: CFA‐induced neuronal IL‐36γ and astrocytic IL‐36R upregulation in the mice spinal cord. Inhibition of spinal IL‐36γ/IL‐36R signaling attenuated the CFA‐induced pain behaviors. IL‐36γ induced IL‐36R/JNK‐dependent pain hypersensitivity.