Interferon‐γ directly induces neurotoxicity through a neuron specific, calcium‐permeable complex of IFN‐γ receptor and AMPA GluRl receptor

Abstract

Interferon-gamma (IFN-gamma) is a proinflammatory cytokine that plays a pivotal role in pathology of diseases in the central nervous system (CNS), such as multiple sclerosis. However, the direct effect of IFN-gamma on neuronal cells has yet to be elucidated. We show here that IFN-gamma directly induces neuronal dysfunction, which appears as dendritic bead formation in mouse cortical neurons and enhances glutamate neurotoxicity mediated via alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptors but not N-methyl-D-aspartate receptors. In the CNS, IFN-gamma receptor forms a unique, neuron-specific, calcium-permeable receptor complex with AMPA receptor subunit GluR1. Through this receptor complex, IFN-gamma phosphorylates GluR1 at serine 845 position by JAK1.2/STAT1 pathway, increases Ca(2+) influx and following nitric oxide production, and subsequently decreases ATP production, leading to the dendritic bead formation. These findings provide novel mechanisms of neuronal excitotoxicity, which may occur in both inflammatory and neurodegenerative diseases in the CNS.

TLR4-activated microglia require IFN-γ to induce severe neuronal dysfunction and death in situ

“…Exposure to IFN-γ alone resulted in different characteristics of microglia, such as higher cell numbers, in line with previously reported findings (15); however, the moderate effects on neuronal function were similar to those of LPS. We did not observe direct toxic effects in situ as has been described for primary cortical neuron cultures (46). The decreased frequency of gamma oscillations might contribute to cognitive deficits and sickness behavior during systemic infections, multiple sclerosis, and Alzheimer's disease featuring increased IFN-γ levels (7,(48)(49)(50).…”

“…In contrast to TLR4, IFN-γ receptors are more abundant and functionally present in microglia, astrocytes, and perhaps in neurons (11,46,47). IFN-γ is a dimerized soluble cytokine and the only member of the type II class of IFNs.…”

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

“…It also serves as a potent inducer of the tryptophancatabolizing enzyme indoleamine-2,3-dioxygenase (IDO) in microglia ultimately leading to the generation of glutamatelike compounds such as QUIN further altering glutamate neurotransmission (Oxenkrug, 2011;Oxenkrug, 2010). IFN-γ may induce neuronal dysfunction by the enhancement of AMPA (but not NMDA)-mediated glutamate neurotoxicity (Mizuno et al, 2008).…”

Neuroprotective intervention by interferon-γ blockade prevents CD8+ T cell-mediated dendrite and synapse loss

“…Several mechanisms may account for this. First, IFN- can reduce cytoplasmic ATP levels (Mizuno et al, 2008), which may induce bioenergetic failure and ionic imbalances. Indeed, reduced ATP production is characteristic of neurons inside MS lesions (Dutta et al, 2006;Mahad et al, 2009;Campbell et al, 2011).…”

“…Indeed, reduced ATP production is characteristic of neurons inside MS lesions (Dutta et al, 2006;Mahad et al, 2009;Campbell et al, 2011). Second, the IFNGR may form a complex with the AMPA receptor subunit GluR1 in neurons, leading to increased excitability and vulnerability to glutamate excitotoxicity (Mizuno et al, 2008). It thus seems plausible that CTL-derived IFN- sensitizes inflamed brain regions to epileptic seizures, which represents the earliest and most prominent manifestation of RE (Rasmussen et al, 1958;Bien et al, 2005).…”