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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doaj-86e23dd663b648c19fd28433ed0ac3212021-06-03T04:35:14ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2021-06-011510.3389/fnins.2021.682451682451Innate Signaling in the CNS Prevents Demyelination in a Focal EAE ModelMagdalena Dubik0Joanna Marczynska1Marlene T. Mørch2Gill Webster3Kirstine Nolling Jensen4Agnieszka Wlodarczyk5Reza Khorooshi6Trevor Owens7Neurobiology, Department of Molecular Medicine, University of Southern Denmark, Odense, DenmarkNeurobiology, Department of Molecular Medicine, University of Southern Denmark, Odense, DenmarkNeurobiology, Department of Molecular Medicine, University of Southern Denmark, Odense, DenmarkInnate Immunotherapeutics, Auckland, New ZealandNeurobiology, Department of Molecular Medicine, University of Southern Denmark, Odense, DenmarkNeurobiology, Department of Molecular Medicine, University of Southern Denmark, Odense, DenmarkNeurobiology, Department of Molecular Medicine, University of Southern Denmark, Odense, DenmarkNeurobiology, Department of Molecular Medicine, University of Southern Denmark, Odense, DenmarkThe 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.https://www.frontiersin.org/articles/10.3389/fnins.2021.682451/fullinnate signalingdemyelinationfocal EAEmyeloid cellsNK cellsT-cells |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Magdalena Dubik Joanna Marczynska Marlene T. Mørch Gill Webster Kirstine Nolling Jensen Agnieszka Wlodarczyk Reza Khorooshi Trevor Owens |
spellingShingle |
Magdalena Dubik Joanna Marczynska Marlene T. Mørch Gill Webster Kirstine Nolling Jensen Agnieszka Wlodarczyk Reza Khorooshi Trevor Owens Innate Signaling in the CNS Prevents Demyelination in a Focal EAE Model Frontiers in Neuroscience innate signaling demyelination focal EAE myeloid cells NK cells T-cells |
author_facet |
Magdalena Dubik Joanna Marczynska Marlene T. Mørch Gill Webster Kirstine Nolling Jensen Agnieszka Wlodarczyk Reza Khorooshi Trevor Owens |
author_sort |
Magdalena Dubik |
title |
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_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_sort |
innate signaling in the cns prevents demyelination in a focal eae model |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Neuroscience |
issn |
1662-453X |
publishDate |
2021-06-01 |
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. |
topic |
innate signaling demyelination focal EAE myeloid cells NK cells T-cells |
url |
https://www.frontiersin.org/articles/10.3389/fnins.2021.682451/full |
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