Regulation of microglial activation by VIP and PACAP: Relevance to traumatic spinal cord injury.

摘要

Traumatic injury to the spinal cord initiates an inflammatory response, which is central to secondary injury following the initial insult. The magnitude and acuity of inflammation following spinal cord injury (SCI) are largely controlled by microglia. Microglia are the intrinsic inflammatory cells in the CNS that are activated upon CNS injury. Activated microglia play an important role in CNS inflammation and autoimmunity. The significance of microglia in CNS inflammations led us to study vasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase-activating polypeptide (PACAP) as potential modulators for microglia. The neuropeptides VIP and PACAP exert anti-inflammatory effects on immune cells. While immunomodulatory actions of VIP/PACAP are well documented in the periphery, whether these effects extend to the CNS has not been investigated. Here, the possibility was explored, with special reference to experimental SCI as a CNS injury paradigm, that the neuropeptides modulate microglia) activation.; Two aspects of microglial activity have been examined for investigating the potential role(s) of VIP/PACAP: production of proinflammatory cytokine tumor necrosis factor-α (TNF-α) and expression of costimulatory molecules CD40 and B7. Rationale for this choice is following: (1) TNF-α is associated with virtually all CNS inflammations and is involved in every aspect of inflammation in CNS injury. (2) Since the concept of T-cell autoimmunity in SCI was raised by Popovich et al. (1996), the ameliorative potential for (autoreactive) T cells has been recognized. Costimulatory molecules are important for possible interactions between T cells and microglia in SCI, and determine consequent fates of T cells and microglia.; The current study shows that TNF-α and costimulatory molecules are upregulated upon SCI possibly through early activation of microglia. The data demonstrate that VIP and PACAP: (1) inhibit the production of TNF-α in injured spinal cords and in activated microglia via a cAMP-dependent pathway. (2) regulate costimulatory molecule expression in activated microglia in part through interleukin-10, a potent anti-inflammatory cytokine.; The final goal of this research was to understand the effects of the neuropeptides on microglial activation in SCI in the context of inflammatory (TNF-α) and autoimmune (costimulatory molecules) cascades initiated by SCI. Showing the anti-inflammatory and immunomodulatory effects of the neuropeptides on microglia, this study may provide a basis for therapeutical intervention in SCI.