Innate Signaling in the CNS Prevents Demyelination in a Focal EAE Model.
NK cells
T-cells
demyelination
focal EAE
innate signaling
myeloid cells
neuroinflammation
Journal
Frontiers in neuroscience
ISSN: 1662-4548
Titre abrégé: Front Neurosci
Pays: Switzerland
ID NLM: 101478481
Informations de publication
Date de publication:
2021
2021
Historique:
received:
18
03
2021
accepted:
07
05
2021
entrez:
21
6
2021
pubmed:
22
6
2021
medline:
22
6
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34149350
doi: 10.3389/fnins.2021.682451
pmc: PMC8209300
doi:
Types de publication
Journal Article
Langues
eng
Pagination
682451Informations de copyright
Copyright © 2021 Dubik, Marczynska, Mørch, Webster, Jensen, Wlodarczyk, Khorooshi and Owens.
Déclaration de conflit d'intérêts
GW was employed by the company Innate Immunotherapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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