Orchestrating Stress Responses in Multiple Sclerosis: A Role for Astrocytic IFNγ Signaling

Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease that is characterized by the infiltration of peripheral immune cells into the central nervous system (CNS), secretion of inflammatory factors, demyelination, and axonal degeneration. Inflammatory mediators such as cytokines alter cellular function and activate resident CNS cells, including astrocytes. Notably, interferon (IFN)γ is a prominent pleiotropic cytokine involved in MS that contributes to disease pathogenesis. Astrocytes are dynamic cells that respond to changes in the cellular microenvironment and are highly responsive to many cytokines, including IFNγ. Throughout the course of MS, intrinsic cell stress is initiated in response to inflammation, which can impact the pathology. It is known that cell stress is pronounced during MS; however, the specific mechanisms relating IFNγ signaling to cell stress responses in astrocytes are still under investigation. This review will highlight the current literature regarding the impact of IFNγ signaling alone and in combination with other immune mediators on astrocyte synthesis of free oxygen radicals and cell death, and cover what is understood regarding astrocytic mitochondrial dysfunction and endoplasmic reticulum stress.