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Neuroprotection by upregulation of the major histocompatibility complex class I (MHC I) in SOD1(G93A) mice
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 interfer...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10498468/ https://www.ncbi.nlm.nih.gov/pubmed/37711512 http://dx.doi.org/10.3389/fncel.2023.1211486 |
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author | Tomiyama, Ana Laura M. R. Cartarozzi, Luciana Politti de Oliveira Coser, Lilian Chiarotto, Gabriela Bortolança Oliveira, Alexandre L. R. |
author_facet | Tomiyama, Ana Laura M. R. Cartarozzi, Luciana Politti de Oliveira Coser, Lilian Chiarotto, Gabriela Bortolança Oliveira, Alexandre L. R. |
author_sort | Tomiyama, Ana Laura M. R. |
collection | PubMed |
description | 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 SOD1(G93A) 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. |
format | Online Article Text |
id | pubmed-10498468 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-104984682023-09-14 Neuroprotection by upregulation of the major histocompatibility complex class I (MHC I) in SOD1(G93A) mice Tomiyama, Ana Laura M. R. Cartarozzi, Luciana Politti de Oliveira Coser, Lilian Chiarotto, Gabriela Bortolança Oliveira, Alexandre L. R. Front Cell Neurosci Neuroscience 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 SOD1(G93A) 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. Frontiers Media S.A. 2023-08-30 /pmc/articles/PMC10498468/ /pubmed/37711512 http://dx.doi.org/10.3389/fncel.2023.1211486 Text en Copyright © 2023 Tomiyama, Cartarozzi, de Oliveira Coser, Chiarotto and Oliveira. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience Tomiyama, Ana Laura M. R. Cartarozzi, Luciana Politti de Oliveira Coser, Lilian Chiarotto, Gabriela Bortolança Oliveira, Alexandre L. R. Neuroprotection by upregulation of the major histocompatibility complex class I (MHC I) in SOD1(G93A) mice |
title | Neuroprotection by upregulation of the major histocompatibility complex class I (MHC I) in SOD1(G93A) mice |
title_full | Neuroprotection by upregulation of the major histocompatibility complex class I (MHC I) in SOD1(G93A) mice |
title_fullStr | Neuroprotection by upregulation of the major histocompatibility complex class I (MHC I) in SOD1(G93A) mice |
title_full_unstemmed | Neuroprotection by upregulation of the major histocompatibility complex class I (MHC I) in SOD1(G93A) mice |
title_short | Neuroprotection by upregulation of the major histocompatibility complex class I (MHC I) in SOD1(G93A) mice |
title_sort | neuroprotection by upregulation of the major histocompatibility complex class i (mhc i) in sod1(g93a) mice |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10498468/ https://www.ncbi.nlm.nih.gov/pubmed/37711512 http://dx.doi.org/10.3389/fncel.2023.1211486 |
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