Unique aspects of IFN‐γ/STAT1 signaling in neurons

Abstract The IFN‐γ/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‐γ/STAT1 pathway is rapidly activated then deactivated to prevent excessive inflammation; however, neurons utilize unique IFN‐γ/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‐γ production in the CNS and how neurons respond to IFN‐γ are unclear. Additionally, it is not well understood how the diversity of the IFN‐γ/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‐γ/STAT1 activation, the potential sources and entry sites of IFN‐γ in the CNS, and the diverse set of homeostatic and pathological effects IFN‐γ/STAT1 signaling in neurons has on CNS health and disease. We will also highlight the different contexts and conditions under which IFN‐γ‐induced STAT1 activation has been studied in neurons, and how various factors might contribute to the vast array of downstream effects observed.