Spinal Il-36 Gamma/Il-36r Participates In The Maintenance Of Chronic Inflammatory Pain Through Astroglial Jnk Pathway

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.