Multiple sclerosis (MS) is a debilitating immune-mediated disease of the brain and spinal cord (the central nervous system [CNS]).
It is characterized by infiltration of the CNS by inflammatory cells and destruction of cells that reside in the CNS, known as oligodendrocytes (ODCs). The soluble factor IFN-gamma has a detrimental effect on disease in patients with MS. However, studies using the mouse model of MS, known as EAE, indicate that IFN-gamma can also have a protective effect. In a study appearing in the February issue of the Journal of Clinical Investigation, researchers from the University of Chicago describe a mechanism by which IFN-gamma protects mice from developing EAE.
Brian Popko and colleagues showed that if IFN-gamma is expressed in the brain before EAE is induced it protects mice from neurodegeneration. IFN-gamma?mediated protection was associated with an increased survival of ODCs and activation of the integrated stress response in ODCs. The ODC integrated stress response, which is triggered in cells by non-optimal environmental conditions, was mediated by PERK, as the beneficial effects of IFN-gamma were lost in PERK-deficient mice. This study describes a mechanism by which IFN-gamma can protect mice from developing EAE and leads the authors to suggest that the timing of IFN-gamma expression in the brain and the extent of the stress response in the ODCs are factors determining whether or not IFN-gamma has a protective or detrimental effect on EAE. Furthermore, they suggest that therapies designed to activate the integrated stress response in ODCs might be beneficial to individuals with MS. However, in an accompanying commentary, Jason Lees and Anne Cross sound a note of warning, saying that “an understanding of these relationships [between the level of IFN-gamma in the brain and the extent of the integrated stress response in ODCs] would be required before attempting to alter ODC stress responses in MS patients for therapeutic benefit.”