Interferon Gamma: Influence on Neural Stem Cell Function in Neurodegenerative and Neuroinflammatory Disease

Abstract

Interferon-gamma (IFNγ), a pleiotropic cytokine, is expressed in diverse neurodegenerative and neuroinflammatory conditions. Its protective mechanisms are well documented during viral infections in the brain, where IFNγ mediates non-cytolytic viral control in infected neurons. However, IFNγ also plays both protective and pathological roles in other central nervous system (CNS) diseases. Of the many neural cells that respond to IFNγ, neural stem/progenitor cells (NSPCs), the only pluripotent cells in the developing and adult brain, are often altered during CNS insults. Recent studies highlight the complex effects of IFNγ on NSPC activity in neurodegenerative diseases. However, the mechanisms that mediate these effects, and the eventual outcomes for the host, are still being explored. Here, we review the effects of IFNγ on NSPC activity during different pathological insults. An improved understanding of the role of IFNγ would provide insight into the impact of immune responses on the progression and resolution of neurodegenerative diseases.

Effects of inflammatory cytokines IFN-γ, TNF-α and IL-6 on the viability and functionality of human pluripotent stem cell-derived neural cells

“…In previous studies, TNF-α has contradictorily been shown to decrease, increase or have no effect on proliferation (Ben-Hur et al, 2003;Wong, Goldshmit and Turnley, 2004;Widera et al, 2006;Johansson, Price and Modo, 2008), while IFN-γ has either decreased or had no effect on proliferation (Ben-Hur et al, 2003;Wong, Goldshmit and Turnley, 2004;Widera et al, 2006;Johansson, Price and Modo, 2008). In consistent with our findings, a recent study showed that IFN-γ signaling via IFNGR1 and IFNGR2 receptors activates the JAK-STAT1 pathway, which eventually inhibits the proliferation of NPCs (Kulkarni, Ganesan and O'Donnell, 2016). TNF-α treatment has been shown to activate the nuclear factor kappa B pathway, which eventually leads to survival of the NPCs (Shih, Wang and Yang, 2015).…”

“…The data about the effects of IFN-γ, TNF-α and IL-6 on neuronal cells is contradictory or has not been studied in details (Ben-Hur et al, 2003;Wong, Goldshmit and Turnley, 2004;Sheng et al, 2005;Widera et al, 2006;Walter et al, 2011;Ye et al, 2013;Kulkarni, Ganesan and O'Donnell, 2016). First, expression of receptors for the cytokines IFN-γ, TNF-α and IL-6 in NPCs were studied; these receptors are necessary to transduce the signals to the cells.…”

Coxsackievirus B3 Infection of Human Neural Progenitor Cells Results in Distinct Expression Patterns of Innate Immune Genes

“…Interestingly, the significant suppression of IFN-γ gene in CVB3-infected hNPCs proved to be an unexpected finding. IFN-γ, a pleiotropic cytokine, has a central role in regulating NSCs proliferation and quiescence [36,37]. Li et al previously demonstrated that K3 and K5 proteins of Kaposi's sarcoma-associated herpesvirus specifically target gamma interferon receptor 1 (IFN-γR1) and induce its ubiquitination, endocytosis, and degradation to downregulate IFN-γR1 surface expression, and, thereby, inhibit IFN-γ action [38].…”

Transcriptome analysis and functional characterization of cerebral organoids in bipolar disorder

“…In comparing the overlap of DEGs with ASD-associated genes, the GO process category that was most significant was "interferon-gamma (IFNγ) signaling." IFNγ has a complex role in mediating immune activation in the central nervous system and is believed to play an important role in the biology of ASD [57,58]. While peripheral cytokine patterns have been noted to be different in BPI, there have been conflicting reports on the role of IFNγ in BPI [59,60].…”