Interferon-α Induces Neurotoxicity Through Activation of the Type I Receptor and the GluN2A Subunit of the NMDA Receptor

Kessing, Cari F.; Tyor, William R.

doi:10.1089/jir.2014.0105

Cited by 28 publications

(18 citation statements)

References 32 publications

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“…However, we acknowledge that the mechanism of IFNα-induced neurotoxicity is not fully understood at this time (Fritz-French and Tyor, 2012; Kessing and Tyor, 2015). IFNα initiates an antiviral response by binding to the type I IFN receptor (IFNAR) with subsequent activation of the JAK/STAT pathway.…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal fluid interferon alpha levels correlate with neurocognitive impairment in ambulatory HIV-Infected individuals

et al. 2016

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HIV-associated neurocognitive disorders (HAND) continue to be common and are associated with increased morbidity and mortality. However, the underlying mechanisms in the combination antiretroviral therapy (cART) era are not fully understood. Interferon alpha (IFNα) is an antiviral cytokine found to be elevated in the cerebrospinal fluid (CSF) of individuals with advanced HIV-associated dementia in the pre-cART era. In this cross-sectional study, we investigated the association between IFNα and neurocognitive performance in ambulatory HIV-infected individuals with milder impairment. An eight test neuropsychological battery representing six cognitive domains was administered. Individual scores were adjusted for demographic characteristics and a composite neuropsychological score (NPT-8) was calculated. IFNα and CSF neurofilament light chain (NFL) levels were measured using enzyme linked immunosorbent assay (ELISA). There were 15 chronically infected participants with a history of significant immunocompromise (median nadir CD4+ of 49 cells/microliter). Most participants were neurocognitively impaired (mean Global Deficit Score of 0.86). CSF IFNα negatively correlated with three individual tests (Trailmaking A, Trailmaking B, and Stroop Color-word) as well as the composite NPT-8 score (r = −0.67, p = 0.006). These negative correlations persisted in multivariable analyses adjusting for chronic hepatitis B and C. Additionally, CSF IFNα correlated strongly with CSF NFL, a marker of neuronal damage (rho = 0.748, p= 0.0013). These results extend findings from individuals with severe HIV-associated dementia in the pre-cART era and suggest that IFNα may continue to play a role in HAND pathogenesis during the cART era. Further investigation into the role of IFNα is indicated.

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Section: Discussionmentioning

confidence: 99%

Cerebrospinal fluid interferon alpha levels correlate with neurocognitive impairment in ambulatory HIV-Infected individuals

et al. 2016

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“…In mouse models, the induction of type I IFN-typical sickness behavior symptoms requires the CNS increase in C-X-C motif chemokine 10 (CXCL10) (Blank et al, 2016), interleukin-6 (IL-6) (Murray et al, 2015) and interleukin-1b (IL-1b) (Field et al, 2010) or decreased tryptophan (TRP) levels (Murakami et al, 2016). IFN-a-induced neurotoxicity was initiated by the simultaneous activation of both the IFNARs and N-methyl D-aspartate receptors (NMDARs), a subtype of glutamate receptor (Kessing & Tyor, 2015). The obtained data indicate that IFN-a rapidly induces a profound shift in whole brain network structure, impairing global functional connectivity and the efficiency of parallel information exchange.…”

Section: T Ype I I Nt Er Fe R Onopath Ies With Impact On Cns F Unctionmentioning

confidence: 99%

“…Resting state functional magnetic resonance imaging (rfMRI) of the whole brain network from patients was performed after systemic IFN-a application in order to analyze changes in brain architecture. Interestingly, despite the fact that IFN-b and IFN-a engage identical receptors, treating neurons in the same experimental setting with IFN-b showed no signs of toxicity based on dendritic arborization assessments (Kessing & Tyor, 2015). Correlations with multiple indices of mood change suggest a role for global changes in brain functional connectivity in behavioral responses to IFN-a (Dipasquale et al, 2015).…”

Section: T Ype I I Nt Er Fe R Onopath Ies With Impact On Cns F Unctionmentioning

confidence: 99%

“…Increased IFN-a levels are responsible for neurotoxicity in patients with neuroinflammatory diseases such as HIV-associated neurocognitive disorders (HAND) (Rho et al, 1995). IFN-a-induced neurotoxicity was initiated by the simultaneous activation of both the IFNARs and N-methyl D-aspartate receptors (NMDARs), a subtype of glutamate receptor (Kessing & Tyor, 2015). Interestingly, despite the fact that IFN-b and IFN-a engage identical receptors, treating neurons in the same experimental setting with IFN-b showed no signs of toxicity based on dendritic arborization assessments (Kessing & Tyor, 2015).…”

Section: T Ype I I Nt Er Fe R Onopath Ies With Impact On Cns F Unctionmentioning

confidence: 99%

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Type I interferon pathway in CNS homeostasis and neurological disorders

Blank

Prinz

2017

Glia

117

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Type I interferons (IFNs), IFN-α and IFN-β, represent the major effector cytokines of the host immune response against viruses and other intracellular pathogens. These cytokines are produced via activation of numerous pattern recognition receptors, including the Toll-like receptor signaling network, retinoic acid-inducible gene-1 (RIG-1), melanoma differentiation-associated protein-5 (MDA-5) and interferon gamma-inducible protein-16 (IFI-16). Whilst the contribution of type I IFNs to peripheral immunity is well documented, they can also be produced by almost every cell in the central nervous system (CNS). Furthermore, IFNs can reach the CNS from the periphery to modulate the function of not only microglia and astrocytes, but also neurons and oligodendrocytes, with major consequences for cognition and behavior. Given the pleiotropic nature of type I IFNs, it is critical to determine their exact cellular impact. Inappropriate upregulation of type I IFN signaling and interferon-stimulated gene expression have been linked to several CNS diseases termed "interferonopathies" including Aicardi-Goutieres syndrome and ubiquitin specific peptidase 18 (USP18)-deficiency. In contrast, in the CNS of mice with virus-induced neuroinflammation, type I IFNs can limit production of other cytokines to prevent potential damage associated with chronic cytokine expression. This capacity of type I IFNs could also explain the therapeutic benefits of exogenous type I IFN in chronic CNS autoimmune diseases such as multiple sclerosis. In this review we will highlight the importance of a well-balanced level of type I IFNs for healthy brain physiology, and to what extent dysregulation of this cytokine system can result in brain 'interferonopathies'.

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“…These evidences suggest that gestational exposure to high-fat and high-sugar diets in murine models results in a disruption of the central reward system, which correlates with epigenetic biomarkers found in addicted-programed subjects. Programming sets the brain to potentiate changes in neuroplasticity [ 97 , 110 ], neuronal death, neurotoxicity [ 111 ], etc., in postnatal life, which leads to the development of cognitive disorders such as addiction [ 112 – 115 ]. It is still under investigation if humans share the aberrant reward plasticity that has been described in murine models.…”

Section: Epigenetic Mechanisms During Fetal Programming and Transgmentioning

confidence: 99%

Maternal Overnutrition Programs Central Inflammation and Addiction-Like Behavior in Offspring

Montalvo-Martínez

Maldonado-Ruiz

Cárdenas-Tueme

et al. 2018

BioMed Research International

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Obesity or maternal overnutrition during pregnancy and lactation might have long-term consequences in offspring health. Fetal programming is characterized by adaptive responses to specific environmental conditions during early life stages. Programming alters gene expression through epigenetic modifications leading to a transgenerational effect of behavioral phenotypes in the offspring. Maternal intake of hypercaloric diets during fetal development programs aberrant behaviors resembling addiction in offspring. Programming by hypercaloric surplus sets a gene expression pattern modulating axonal pruning, synaptic signaling, and synaptic plasticity in selective regions of the reward system. Likewise, fetal programming can promote an inflammatory phenotype in peripheral and central sites through different cell types such as microglia and T and B cells, which contribute to disrupted energy sensing and behavioral pathways. The molecular mechanism that regulates the central and peripheral immune cross-talk during fetal programming and its relevance on offspring's addictive behavior susceptibility is still unclear. Here, we review the most relevant scientific reports about the impact of hypercaloric nutritional fetal programming on central and peripheral inflammation and its effects on addictive behavior of the offspring.

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Interferon-α Induces Neurotoxicity Through Activation of the Type I Receptor and the GluN2A Subunit of the NMDA Receptor

Cited by 28 publications

References 32 publications

Cerebrospinal fluid interferon alpha levels correlate with neurocognitive impairment in ambulatory HIV-Infected individuals

Cerebrospinal fluid interferon alpha levels correlate with neurocognitive impairment in ambulatory HIV-Infected individuals

Type I interferon pathway in CNS homeostasis and neurological disorders

Maternal Overnutrition Programs Central Inflammation and Addiction-Like Behavior in Offspring

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