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.

Human in vivo evidence of reduced astrocyte activation and neuroinflammation in patients with treatment‐resistant depression following electroconvulsive therapy

“…IFN‐γ's interaction with microglia and astrocytes in the CNS is crucial for the regulation of neuroinflammatory processes 97 . Moreover, different studies have highlighted the important role of IFN‐γ on the regulation of neurons 98–100 . Rodent research suggests that priming of microglia with IFN‐γ impairs adult hippocampal neurogenesis and leads to depression‐like behaviors and cognitive defects 101 .…”

“…97 Moreover, different studies have highlighted the important role of IFN-γ on the regulation of neurons. [98][99][100] Rodent research suggests that priming of microglia with IFN-γ impairs adult hippocampal neurogenesis and leads to depression-like behaviors and cognitive defects. 101 Conversely, absence of IFN-γ promotes hippocampal plasticity and enhances cognitive performance.…”

Blood RNA‐sequencing analysis in acrylamide‐induced neurotoxicity and depressive symptoms in rats

“…41 INF-γ signaling occurs through INF-γ receptor and can be observed in microglia. 42,43 The binding of IFN-γ to the receptor activates the canonical JAK/STAT1 pathway, resulting in the direct activation of the transcription of various genes in macrophages. In addition, IFN-γ moderately increases the level of the microglial activation marker iNOS but not TNF-α.…”

“…49 The dendrites, cell body, and synapses of neurons, IFN-γ/STAT1 signaling operates through noncanonical mechanisms of rapid and site-specific action, and interaction with GABAergic and glutamatergic receptors to modulate neuronal activity. 43,50 Therefore, IFN-γ signaling in neurons may help maintain the excitation-inhibitory characterized by raising levels of IFN-γ, transduction from the bloodbrain barrier, and infiltration of T lymphocytes into parenchymal tissues. These phenomena occur to varying degrees in major depressive symptoms.…”

“…INF‐γ priming of microglia in proliferation, increased synapse elimination, assuage NO release, gamma band activity, and cognitive function 41 . INF‐γ signaling occurs through INF‐γ receptor and can be observed in microglia 42,43 . The binding of IFN‐γ to the receptor activates the canonical JAK/STAT1 pathway, resulting in the direct activation of the transcription of various genes in macrophages.…”