Unique aspects of IFN-gamma/STAT1 signaling in neurons

The IFN-gamma/STAT1 immune signaling pathway impacts many homeostatic and pathological aspects of neurons, beyond its canonical role in controlling intracellular pathogens. Well known for its potent pro-inflammatory and anti-viral functions in the periphery, the IFN-gamma/STAT1 pathway is rapidly activated then deactivated to prevent excessive inflammation; however, neurons utilize unique IFN-gamma/STAT1 activation patterns, which may contribute to the non-canonical neuron-specific downstream effects. Though it is now well-established that the immune system interacts and supports the CNS in health and disease, many aspects regarding IFN-gamma production in the CNS and how neurons respond to IFN-gamma are unclear. Additionally, it is not well understood how the diversity of the IFN-gamma/STAT1 pathway is regulated in neurons to control homeostatic functions, support immune surveillance, and prevent pathologies. In this review, we discuss the neuron-specific mechanisms and kinetics of IFN-gamma/STAT1 activation, the potential sources and entry sites of IFN-gamma in the CNS, and the diverse set of homeostatic and pathological effects IFN-gamma/STAT1 signaling in neurons has on CNS health and disease. We will also highlight the different contexts and conditions under which IFN-gamma-induced STAT1 activation has been studied in neurons, and how various factors might contribute to the vast array of downstream effects observed.