Type I/II Interferon Balance in the Regulation of Brain Physiology and Pathology

Recent findings have revealed distinct roles for type I and II interferons (IFN-I and IFN-γ) in the recruitment of immune cells to the central nervous system (CNS) and highlighted the importance of this process for brain maintenance and protection/repair. Furthermore, manipulation of IFN-I and IFN-γ pathways in pathological contexts has yielded conflicting results. We discuss these findings, focusing on two distinct conditions; relapsing remitting multiple sclerosis (RRMS) and brain aging. Using these examples, we propose that regulation of immune cell entry to the CNS is a mechanism through which interaction between IFN-I and -II can affect brain function from its anatomical borders. Deviation from homeostatic IFN-I/-II balance may contribute to distinct brain pathologies, resulting from either insufficient immune surveillance of the CNS and loss of immune-dependent protection, or overwhelming leukocyte entry and immune-mediated destruction.

TrendsHomeostasis: IFN-γ signaling at the choroid plexus within the brain controls CNS immune surveillance important for brain maintenance.Relapsing remitting multiple sclerosis: endogenously expressed as well as therapeutically delivered IFN-I ameliorates disease progression by indirectly attenuating IFN-γ signaling at the borders of the brain and restraining excess infiltration of pathological immune cells to the CNS.Aging: excess expression of IFN-I by the CNS choroid plexus is associated with insufficient IFN-γ dependent CNS immune surveillance as well as with loss of cognitive function and neurogenesis.