Astroglioma conditioned medium increases synaptic elimination and correlates with major histocompatibility complex of class I (MHC I) upregulation in PC12Cells

Inácio, Rodrigo Fabrizzio; Zanon, Renata Graciele; Castro, Mateus Vidigal de; Souza, Henrique Marques de; Bajgelman, Marcio C.; Verinaud, Liana; Oliveira, Alexandre Leite Rodrigues de

doi:10.1016/j.neulet.2016.10.019

Cited by 6 publications

(4 citation statements)

References 22 publications

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“…In sharp contrast, IFN-β treatment increased the number of GFAP-positive cells in the brains of wild-type mice [209] and in primary mouse astrocyte cultures [230]. In addition, in increased major histocompatibility complex class I (MHC-I), protein levels were found in IFN-β-treated NG97 astrocyte cells [231]. In addition, the protein levels and secretion of A1 astrocyte-related factors such as CXCL10, IL-6, CCL5 increased both in vitro [230] and in vivo [232] following the treatment with IFN-β or the induction of IFN-β via poly I:C administration.…”

Section: Astrocytesmentioning

confidence: 98%

Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

Kleijn

Martens

2020

IJMS

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Multiple sclerosis (MS) is characterized by peripheral and central inflammatory features, as well as demyelination and neurodegeneration. The available Food and Drug Administration (FDA)-approved drugs for MS have been designed to suppress the peripheral immune system. In addition, however, the effects of these drugs may be partially attributed to their influence on glial cells and neurons of the central nervous system (CNS). We here describe the molecular effects of the traditional and more recent FDA-approved MS drugs Fingolimod, Dimethyl Fumarate, Glatiramer Acetate, Interferon-β, Teriflunomide, Laquinimod, Natalizumab, Alemtuzumab and Ocrelizumab on microglia, astrocytes, neurons and oligodendrocytes. Furthermore, we point to a possible common molecular effect of these drugs, namely a key role for NFκB signaling, causing a switch from pro-inflammatory microglia and astrocytes to anti-inflammatory phenotypes of these CNS cell types that recently emerged as central players in MS pathogenesis. This notion argues for the need to further explore the molecular mechanisms underlying MS drug action.

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Section: Astrocytesmentioning

confidence: 98%

Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

Kleijn

Martens

2020

IJMS

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“…We have proposed that this mechanism underlies the injury of demyelinated axons in multiple sclerosis (MS) 1, 2, 4, 10. Evidence also suggests that MHC I is involved with synaptic pruning during cortical development12, 13, 14, 16, 17, 18, 19, 20, 21 and following injury22, 23, 24, 25 and contributes to neuronal plasticity 16, 17, 26, 27. These findings also suggest that retrogradely induced MHC class I may contribute to the diffuse synaptopathy observed in MS and other neurodegenerative diseases 28, 29, 30, 31, 32, 33, 34, 35.…”

Section: Introductionmentioning

confidence: 99%

Retrograde interferon‐gamma signaling induces major histocompatibility class I expression in human‐induced pluripotent stem cell‐derived neurons

Clarkson

Patel

LaFrance‐Corey

et al. 2017

Ann Clin Transl Neurol

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ObjectiveInjury‐associated axon‐intrinsic signals are thought to underlie pathogenesis and progression in many neuroinflammatory and neurodegenerative diseases, including multiple sclerosis (MS). Retrograde interferon gamma (IFN γ) signals are known to induce expression of major histocompatibility class I (MHC I) genes in murine axons, thereby increasing the susceptibility of these axons to attack by antigen‐specific CD8+ T cells. We sought to determine whether the same is true in human neurons.MethodsA novel microisolation chamber design was used to physically isolate and manipulate axons from human skin fibroblast‐derived induced pluripotent stem cell (iPSC)‐derived neuron‐enriched neural aggregates. Fluorescent retrobeads were used to assess the fraction of neurons with projections to the distal chamber. Axons were treated with IFN γ for 72 h and expression of MHC class I and antigen presentation genes were evaluated by RT‐PCR and immunofluorescence.ResultsHuman iPSC‐derived neural stem cells maintained as 3D aggregate cultures in the cell body chamber of polymer microisolation chambers extended dense axonal projections into the fluidically isolated distal chamber. Treatment of these axons with IFN γ resulted in upregulation of MHC class I and antigen processing genes in the neuron cell bodies. IFN γ‐induced MHC class I molecules were also anterogradely transported into the distal axon.InterpretationThese results provide conclusive evidence that human axons are competent to express MHC class I molecules, suggesting that inflammatory factors enriched in demyelinated lesions may render axons vulnerable to attack by autoreactive CD8+ T cells in patients with MS. Future work will be aimed at identifying pathogenic anti‐axonal T cells in these patients.

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“…Major histocompatibility complex of class I is a transmembrane heterodimer cell surface receptor, composed of an α chain, which is folded into three extracellular globular domains (α1, α2, and α3) coupled to the obligatory β2 microglobulin (β2 m) subunit ( Maenaka and Jones, 1999 ). In addition to the well-established role in the immune system, it has become clear that MHC-I plays a non-immune role in CNS development ( Elmer and McAllister, 2012 ), and is involved in mechanisms of synaptic plasticity and axonal regeneration ( Corriveau et al, 1998 ; Oliveira et al, 2004 ; Castelli-Haley et al, 2010 ; Zanon et al, 2010 ; Inácio et al, 2012 ; Goodin, 2013 ; Cebrian et al, 2014 ; Lee et al, 2014 ; Mahurkar et al, 2014 ; Bombeiro et al, 2016 , 2017 ; Inacio et al, 2016 ; Cartarozzi et al, 2019 ), acting as a neuron-neuron and neuron-glia communication mechanism, modulating the cellular response to injury and disease ( Oliveira et al, 2004 ; Zanon and Oliveira, 2006 ).…”

Section: Introductionmentioning

confidence: 99%

Neuroprotection by upregulation of the major histocompatibility complex class I (MHC I) in SOD1G93A mice

Tomiyama,

Cartarozzi,

de Oliveira Coser

et al. 2023

Front. Cell. Neurosci.

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that progressively affects motoneurons, causing muscle atrophy and evolving to death. Astrocytes inhibit the expression of MHC-I by neurons, contributing to a degenerative outcome. The present study verified the influence of interferon β (IFN β) treatment, a proinflammatory cytokine that upregulates MHC-I expression, in SOD1G93A transgenic mice. For that, 17 days old presymptomatic female mice were subjected to subcutaneous application of IFN β (250, 1,000, and 10,000 IU) every other day for 20 days. Rotarod motor test, clinical score, and body weight assessment were conducted every third day throughout the treatment period. No significant intergroup variations were observed in such parameters during the pre-symptomatic phase. All mice were then euthanized, and the spinal cords collected for comparative analysis of motoneuron survival, reactive gliosis, synapse coverage, microglia morphology classification, cytokine analysis by flow cytometry, and RT–qPCR quantification of gene transcripts. Additionally, mice underwent Rotarod motor assessment, weight monitoring, and neurological scoring. The results show that IFN β treatment led to an increase in the expression of MHC-I, which, even at the lowest dose (250 IU), resulted in a significant increase in neuronal survival in the ALS presymptomatic period which lasted until the onset of the disease. The treatment also influenced synaptic preservation by decreasing excitatory inputs and upregulating the expression of AMPA receptors by astrocytes. Microglial reactivity quantified by the integrated density of pixels did not decrease with treatment but showed a less activated morphology, coupled with polarization to an M1 profile. Disease progression upregulated gene transcripts for pro- and anti-inflammatory cytokines, and IFN β treatment significantly decreased mRNA expression for IL4. Overall, the present results demonstrate that a low dosage of IFN β shows therapeutic potential by increasing MHC-I expression, resulting in neuroprotection and immunomodulation.

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Astroglioma conditioned medium increases synaptic elimination and correlates with major histocompatibility complex of class I (MHC I) upregulation in PC12Cells

Cited by 6 publications

References 22 publications

Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

Retrograde interferon‐gamma signaling induces major histocompatibility class I expression in human‐induced pluripotent stem cell‐derived neurons

Neuroprotection by upregulation of the major histocompatibility complex class I (MHC I) in SOD1G93A mice

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