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Experimental Demyelination and Axonal Loss Are Reduced in MicroRNA-146a Deficient Mice

BACKGROUND: The cuprizone (CPZ) model of multiple sclerosis (MS) was used to identify microRNAs (miRNAs) related to in vivo de- and remyelination. We further investigated the role of miR-146a in miR-146a-deficient (KO) mice: this miRNA is differentially expressed in MS lesions and promotes different...

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Autores principales: Martin, Nellie A., Molnar, Viktor, Szilagyi, Gabor T., Elkjaer, Maria L., Nawrocki, Arkadiusz, Okarmus, Justyna, Wlodarczyk, Agnieszka, Thygesen, Eva K., Palkovits, Miklos, Gallyas, Ferenc, Larsen, Martin R., Lassmann, Hans, Benedikz, Eirikur, Owens, Trevor, Svenningsen, Asa F., Illes, Zsolt
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857529/
https://www.ncbi.nlm.nih.gov/pubmed/29593734
http://dx.doi.org/10.3389/fimmu.2018.00490
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author Martin, Nellie A.
Molnar, Viktor
Szilagyi, Gabor T.
Elkjaer, Maria L.
Nawrocki, Arkadiusz
Okarmus, Justyna
Wlodarczyk, Agnieszka
Thygesen, Eva K.
Palkovits, Miklos
Gallyas, Ferenc
Larsen, Martin R.
Lassmann, Hans
Benedikz, Eirikur
Owens, Trevor
Svenningsen, Asa F.
Illes, Zsolt
author_facet Martin, Nellie A.
Molnar, Viktor
Szilagyi, Gabor T.
Elkjaer, Maria L.
Nawrocki, Arkadiusz
Okarmus, Justyna
Wlodarczyk, Agnieszka
Thygesen, Eva K.
Palkovits, Miklos
Gallyas, Ferenc
Larsen, Martin R.
Lassmann, Hans
Benedikz, Eirikur
Owens, Trevor
Svenningsen, Asa F.
Illes, Zsolt
author_sort Martin, Nellie A.
collection PubMed
description BACKGROUND: The cuprizone (CPZ) model of multiple sclerosis (MS) was used to identify microRNAs (miRNAs) related to in vivo de- and remyelination. We further investigated the role of miR-146a in miR-146a-deficient (KO) mice: this miRNA is differentially expressed in MS lesions and promotes differentiation of oligodendrocyte precursor cells (OPCs) during remyelination, but its role has not been examined during demyelination. METHODS: MicroRNAs were examined by Agilent Mouse miRNA Microarray in the corpus callosum during CPZ-induced demyelination and remyelination. Demyelination, axonal loss, changes in number of oligodendrocytes, OPCs, and macrophages/microglia was compared by histology/immunohistochemistry between KO and WT mice. Differential expression of target genes and proteins of miR-146a was analyzed in the transcriptome (4 × 44K Agilent Whole Mouse Genome Microarray) and proteome (liquid chromatography tandem mass spectrometry) of CPZ-induced de- and remyelination in WT mice. Levels of proinflammatory molecules in the corpus callosum were compared in WT versus KO mice by Meso Scale Discovery multiplex protein analysis. RESULTS: miR-146a was increasingly upregulated during CPZ-induced de- and remyelination. The absence of miR-146a in KO mice protected against demyelination, axonal loss, body weight loss, and atrophy of thymus and spleen. The number of CNP(+) oligodendrocytes was increased during demyelination in the miR-146a KO mice, while there was a trend of increased number of NG2(+) OPCs in the WT mice. miR-146a target genes, SNAP25 and SMAD4, were downregulated in the proteome of demyelinating corpus callosum in WT mice. Higher levels of SNAP25 were measured by ELISA in the corpus callosum of miR-146a KO mice, but there was no difference between KO and WT mice during demyelination. Multiplex protein analysis of the corpus callosum lysate revealed upregulated TNF-RI, TNF-RII, and CCL2 in the WT mice in contrast to KO mice. The number of Mac3(+) and Iba1(+) macrophages/microglia was reduced in the demyelinating corpus callosum of the KO mice. CONCLUSION: During demyelination, absence of miR-146a reduced inflammatory responses, demyelination, axonal loss, the number of infiltrating macrophages, and increased the number of myelinating oligodendrocytes. The number of OPCs was slightly higher in the WT mice during remyelination, indicating a complex role of miR-146a during in vivo de- and remyelination.
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spelling pubmed-58575292018-03-28 Experimental Demyelination and Axonal Loss Are Reduced in MicroRNA-146a Deficient Mice Martin, Nellie A. Molnar, Viktor Szilagyi, Gabor T. Elkjaer, Maria L. Nawrocki, Arkadiusz Okarmus, Justyna Wlodarczyk, Agnieszka Thygesen, Eva K. Palkovits, Miklos Gallyas, Ferenc Larsen, Martin R. Lassmann, Hans Benedikz, Eirikur Owens, Trevor Svenningsen, Asa F. Illes, Zsolt Front Immunol Immunology BACKGROUND: The cuprizone (CPZ) model of multiple sclerosis (MS) was used to identify microRNAs (miRNAs) related to in vivo de- and remyelination. We further investigated the role of miR-146a in miR-146a-deficient (KO) mice: this miRNA is differentially expressed in MS lesions and promotes differentiation of oligodendrocyte precursor cells (OPCs) during remyelination, but its role has not been examined during demyelination. METHODS: MicroRNAs were examined by Agilent Mouse miRNA Microarray in the corpus callosum during CPZ-induced demyelination and remyelination. Demyelination, axonal loss, changes in number of oligodendrocytes, OPCs, and macrophages/microglia was compared by histology/immunohistochemistry between KO and WT mice. Differential expression of target genes and proteins of miR-146a was analyzed in the transcriptome (4 × 44K Agilent Whole Mouse Genome Microarray) and proteome (liquid chromatography tandem mass spectrometry) of CPZ-induced de- and remyelination in WT mice. Levels of proinflammatory molecules in the corpus callosum were compared in WT versus KO mice by Meso Scale Discovery multiplex protein analysis. RESULTS: miR-146a was increasingly upregulated during CPZ-induced de- and remyelination. The absence of miR-146a in KO mice protected against demyelination, axonal loss, body weight loss, and atrophy of thymus and spleen. The number of CNP(+) oligodendrocytes was increased during demyelination in the miR-146a KO mice, while there was a trend of increased number of NG2(+) OPCs in the WT mice. miR-146a target genes, SNAP25 and SMAD4, were downregulated in the proteome of demyelinating corpus callosum in WT mice. Higher levels of SNAP25 were measured by ELISA in the corpus callosum of miR-146a KO mice, but there was no difference between KO and WT mice during demyelination. Multiplex protein analysis of the corpus callosum lysate revealed upregulated TNF-RI, TNF-RII, and CCL2 in the WT mice in contrast to KO mice. The number of Mac3(+) and Iba1(+) macrophages/microglia was reduced in the demyelinating corpus callosum of the KO mice. CONCLUSION: During demyelination, absence of miR-146a reduced inflammatory responses, demyelination, axonal loss, the number of infiltrating macrophages, and increased the number of myelinating oligodendrocytes. The number of OPCs was slightly higher in the WT mice during remyelination, indicating a complex role of miR-146a during in vivo de- and remyelination. Frontiers Media S.A. 2018-03-12 /pmc/articles/PMC5857529/ /pubmed/29593734 http://dx.doi.org/10.3389/fimmu.2018.00490 Text en Copyright © 2018 Martin, Molnar, Szilagyi, Elkjaer, Nawrocki, Okarmus, Wlodarczyk, Thygesen, Palkovits, Gallyas, Larsen, Lassmann, Benedikz, Owens, Svenningsen and Illes. http://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 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 Immunology
Martin, Nellie A.
Molnar, Viktor
Szilagyi, Gabor T.
Elkjaer, Maria L.
Nawrocki, Arkadiusz
Okarmus, Justyna
Wlodarczyk, Agnieszka
Thygesen, Eva K.
Palkovits, Miklos
Gallyas, Ferenc
Larsen, Martin R.
Lassmann, Hans
Benedikz, Eirikur
Owens, Trevor
Svenningsen, Asa F.
Illes, Zsolt
Experimental Demyelination and Axonal Loss Are Reduced in MicroRNA-146a Deficient Mice
title Experimental Demyelination and Axonal Loss Are Reduced in MicroRNA-146a Deficient Mice
title_full Experimental Demyelination and Axonal Loss Are Reduced in MicroRNA-146a Deficient Mice
title_fullStr Experimental Demyelination and Axonal Loss Are Reduced in MicroRNA-146a Deficient Mice
title_full_unstemmed Experimental Demyelination and Axonal Loss Are Reduced in MicroRNA-146a Deficient Mice
title_short Experimental Demyelination and Axonal Loss Are Reduced in MicroRNA-146a Deficient Mice
title_sort experimental demyelination and axonal loss are reduced in microrna-146a deficient mice
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857529/
https://www.ncbi.nlm.nih.gov/pubmed/29593734
http://dx.doi.org/10.3389/fimmu.2018.00490
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