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Innate Signaling in the CNS Prevents Demyelination in a Focal EAE Model

The pathological hallmark of multiple sclerosis (MS) is the formation of multifocal demyelinating lesions in the central nervous system (CNS). Stimulation of innate receptors has been shown to suppress experimental autoimmune encephalomyelitis (EAE), an MS-like disease in mice. Specifically, targeti...

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Autores principales: Dubik, Magdalena, Marczynska, Joanna, Mørch, Marlene T., Webster, Gill, Jensen, Kirstine Nolling, Wlodarczyk, Agnieszka, Khorooshi, Reza, Owens, Trevor
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209300/
https://www.ncbi.nlm.nih.gov/pubmed/34149350
http://dx.doi.org/10.3389/fnins.2021.682451
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author Dubik, Magdalena
Marczynska, Joanna
Mørch, Marlene T.
Webster, Gill
Jensen, Kirstine Nolling
Wlodarczyk, Agnieszka
Khorooshi, Reza
Owens, Trevor
author_facet Dubik, Magdalena
Marczynska, Joanna
Mørch, Marlene T.
Webster, Gill
Jensen, Kirstine Nolling
Wlodarczyk, Agnieszka
Khorooshi, Reza
Owens, Trevor
author_sort Dubik, Magdalena
collection PubMed
description The pathological hallmark of multiple sclerosis (MS) is the formation of multifocal demyelinating lesions in the central nervous system (CNS). Stimulation of innate receptors has been shown to suppress experimental autoimmune encephalomyelitis (EAE), an MS-like disease in mice. Specifically, targeting Toll-like receptor 9 (TLR9) and NOD-like receptor 2 (NOD2) significantly reduced disease severity. In the present work we have developed a novel focal EAE model to further study the effect of innate signaling on demyelinating pathology. Focal lesions were induced by stereotactic needle insertion into the corpus callosum (CC) of mice previously immunized for EAE. This resulted in focal pathology characterized by infiltration and demyelination in the CC. We find that intrathecal delivery of MIS416, a TLR9 and NOD2 bispecific innate ligand, into the cerebrospinal fluid reduced focal lesions in the CC. This was associated with upregulation of type I and II interferons, interleukin-10, arginase-1, CCL-2 and CXCL-10. Analysis of draining cervical lymph nodes showed upregulation of type II interferons and interleukin 10. Moreover, intrathecal MIS416 altered the composition of early CNS infiltrates, increasing proportions of myeloid and NK cells and reducing T cells at the lesion site. This study contributes to an increased understanding of how innate immune responses can play a protective role, which in turn may lead to additional therapeutic strategies for the prevention and treatment of demyelinating pathologies.
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spelling pubmed-82093002021-06-18 Innate Signaling in the CNS Prevents Demyelination in a Focal EAE Model Dubik, Magdalena Marczynska, Joanna Mørch, Marlene T. Webster, Gill Jensen, Kirstine Nolling Wlodarczyk, Agnieszka Khorooshi, Reza Owens, Trevor Front Neurosci Neuroscience The pathological hallmark of multiple sclerosis (MS) is the formation of multifocal demyelinating lesions in the central nervous system (CNS). Stimulation of innate receptors has been shown to suppress experimental autoimmune encephalomyelitis (EAE), an MS-like disease in mice. Specifically, targeting Toll-like receptor 9 (TLR9) and NOD-like receptor 2 (NOD2) significantly reduced disease severity. In the present work we have developed a novel focal EAE model to further study the effect of innate signaling on demyelinating pathology. Focal lesions were induced by stereotactic needle insertion into the corpus callosum (CC) of mice previously immunized for EAE. This resulted in focal pathology characterized by infiltration and demyelination in the CC. We find that intrathecal delivery of MIS416, a TLR9 and NOD2 bispecific innate ligand, into the cerebrospinal fluid reduced focal lesions in the CC. This was associated with upregulation of type I and II interferons, interleukin-10, arginase-1, CCL-2 and CXCL-10. Analysis of draining cervical lymph nodes showed upregulation of type II interferons and interleukin 10. Moreover, intrathecal MIS416 altered the composition of early CNS infiltrates, increasing proportions of myeloid and NK cells and reducing T cells at the lesion site. This study contributes to an increased understanding of how innate immune responses can play a protective role, which in turn may lead to additional therapeutic strategies for the prevention and treatment of demyelinating pathologies. Frontiers Media S.A. 2021-06-03 /pmc/articles/PMC8209300/ /pubmed/34149350 http://dx.doi.org/10.3389/fnins.2021.682451 Text en Copyright © 2021 Dubik, Marczynska, Mørch, Webster, Jensen, Wlodarczyk, Khorooshi and Owens. 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
Dubik, Magdalena
Marczynska, Joanna
Mørch, Marlene T.
Webster, Gill
Jensen, Kirstine Nolling
Wlodarczyk, Agnieszka
Khorooshi, Reza
Owens, Trevor
Innate Signaling in the CNS Prevents Demyelination in a Focal EAE Model
title Innate Signaling in the CNS Prevents Demyelination in a Focal EAE Model
title_full Innate Signaling in the CNS Prevents Demyelination in a Focal EAE Model
title_fullStr Innate Signaling in the CNS Prevents Demyelination in a Focal EAE Model
title_full_unstemmed Innate Signaling in the CNS Prevents Demyelination in a Focal EAE Model
title_short Innate Signaling in the CNS Prevents Demyelination in a Focal EAE Model
title_sort innate signaling in the cns prevents demyelination in a focal eae model
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209300/
https://www.ncbi.nlm.nih.gov/pubmed/34149350
http://dx.doi.org/10.3389/fnins.2021.682451
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