GM-CSF licenses microglia to mediate tissue damage in the CNS

[摘要] Granulocyte-macrophage colony stimulating factor (GM-CSF) plays multiple roles in the development, maintenance and regulation of the immune system.In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), the absence of GM-CSF expression by CNS antigen-specific Th1/17 T cells abolishes their encephalitogenic potential; an effect attributed to the inability of GM-CSF-/- T cells to activate myeloid cells within the CNS. To address the mechanisms involved, we investigated the effects of GM-CSF in myelinated cultures derived from embryonic mouse spinal cord. Our data demonstrate GM-CSF “activates” microglia inducing marked changes in morphology and enhancing their phagocytic potential. However, in isolation, this is unable to damage myelin or axons. These data suggest GM-CSF synergises with other effector mechanisms to mediate tissue damage in EAE. We therefore investigated its ability to potentiate the cytopathic effects of IFN-γ and TNF-α, two pro-inflammatory cytokines associated with EAE and MS pathogenesis. We report a combination of all three cytokines is required to induce rapid and extensive cell death. Cell death was associated with induction of iNOS in microglia, elevated nitric oxide and was inhibited completely by an iNOS inhibitor, AMT hydrochloride. Additionally, cell supernatant analyses revealed that the synergy between GM-CSF, IFN-γ and TNF-α is also responsible for extensive pro-inflammatory cytokines release, including IL-6 and IL-1β.

[发布机构] University:University of Glasgow;Department:Institute of Infection Immunity and Inflammation

[关键词] GM-CSF, multiple sclerosis, experimental autoimmune enchephalomyelitis, neuroinflammation, microglia.