Modulation of microglial/macrophage activation by macrophage inhibitory factor (TKP) or tuftsin (TKPR) attenuates the disease course of experimental autoimmune encephalomyelitis.

BACKGROUND: Myelin Oligodendrocyte Glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) is the most commonly used mouse model for multiple sclerosis (MS). During the of progression of EAE, microglia, the immunocompetent cells of the brain, become activated and accumulate around demyelinated lesions. Microglial activation is mediated by the extracellular protease tissue Plasminogen Activator (tPA), and mice lacking tPA display altered EAE progression. In this study, we have used pharmacological inhibitors and stimulators of microglial/macrophage activation to examine the temporal requirement for microglial activation in EAE progression and to determine whether such approaches might potentially be of therapeutic value. RESULTS: Intervention using the tripeptide macrophage/microglia inhibitory factor MIF (TKP) and the tetrapeptide macrophage/microglial stimulator tuftsin (TKPR) attenuated EAE symptoms and revealed that the timing of macrophage/microglial activation is critical for the clinical outcome of EAE. We show that the disease progression can potentially be manipulated favorably at early stages by altering the timing of microglial activation, which in turn alters the systemic immune response to favor upregulation of T helper cell 2 genes that promote recovery from EAE. CONCLUSION: Preventative and therapeutic modulation of macrophage/microglial activity significantly alters the outcome of EAE at symptomatic stages. Specific molecular targets have been identified that represent potential avenues of exploration for the treatment and prevention of MS.

Involvement of tissue plasminogen activator in onset and effector phases of experimental allergic encephalomyelitis.

Inflammation, demyelination, and neurodegeneration are pathological features of multiple sclerosis (MS). In the brains of MS patients, tissue plasminogen activator (tPA) mRNA and protein are upregulated, and changes in the levels of tPA correlate with progression of the disease. However, the role of tPA in MS is as yet unknown. tPA functions in the CNS in neuronal plasticity and cell death. tPA also mediates the activation of microglia, the CNS "immune cells." In this study, we establish that tPA activity increases during major oligodendrocyte glycoprotein-induced experimental allergic encephalomyelitis (EAE) in normal mice. To explore the role of tPA in this disease as a model for MS, we have examined the EAE course and expression of histopathological markers in mice lacking tPA (tPA(-/-)). We find that tPA(-/-) mice have a delayed onset of EAE but then exhibit increased severity and delayed recovery from the neurological dysfunction. Demyelination and axon degeneration are delayed, microglial activation is attenuated, and the production of chemokines is decreased. Our results suggest that tPA and activated microglia have complex roles in MS/EAE, and that these roles are harmful during the onset of the disease but beneficial in the recovery phase. A temporally restricted attenuation of tPA activity could have therapeutic potential in the management of MS.