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.


CONCLUSIONS
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.
Bhasin
Madhuri
M
Genetics, Department of Pharmacological Sciences, University Medical Center at Stony Brook, Stony Brook, NY 11794-8651, USA. bhasin@pharm.stonybrook.edu <bhasin@pharm.stonybrook.edu>
Wu
Muzhou
M
Tsirka
Stella E
SE
D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D005260:Female; D007114:Immunization / Q000379:methods; D007155:Immunologic Factors; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008263:Macrophage Migration-Inhibitory Factors / Q000008:administration & dosage* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D009185:Myelin Proteins; D009186:Myelin Sheath / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018992:Myelin-Associated Glycoprotein / Q000737:chemistry / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D014405:Tuftsin / Q000008:administration & dosage* / Q000378:metabolism
D007155:Immunologic Factors; D008263:Macrophage Migration-Inhibitory Factors; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D010959:Tissue Plasminogen Activator; D014405:Tuftsin