Synergistic Targeting of Innate Receptors TLR7 and NOD2 for Therapeutic Intervention in Multiple Sclerosis
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Published:2024-07-07
Issue:13
Volume:25
Page:7462
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Dubik Magdalena1ORCID, Marczynska-Grzelak Joanna1, Sørensen Michael Zaucha1, Dieu Ruthe Storgaard1, Rusin Dominika1, Schiöth Eydís Sigurdardóttir1ORCID, Ramazani Bita1, Belal Rouhin1, Ojha Bhavya1ORCID, Krieger Jonathan1, Arengoth Dina S.1, Wlodarczyk Agnieszka1ORCID, Owens Trevor1, Khorooshi Reza1ORCID
Affiliation:
1. Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Campusvej 55, DK-5000 Odense C, Denmark
Abstract
Regulation of neuroinflammation is critical for maintaining central nervous system (CNS) homeostasis and holds therapeutic promise in autoimmune diseases such as multiple sclerosis (MS). Previous studies have highlighted the significance of selective innate signaling in triggering anti-inflammatory mechanisms, which play a protective role in an MS-like disease, experimental autoimmune encephalomyelitis (EAE). However, the individual intra-CNS administration of specific innate receptor ligands or agonists, such as for toll-like receptor 7 (TLR7) and nucleotide-binding oligomerization-domain-containing protein 2 (NOD2), failed to elicit the desired anti-inflammatory response in EAE. In this study, we investigated the potential synergistic effect of targeting both TLR7 and NOD2 simultaneously to prevent EAE progression. Our findings demonstrate that simultaneous intrathecal administration of NOD2- and TLR7-agonists led to synergistic induction of Type I IFN (IFN I) and effectively suppressed EAE in an IFN I-dependent manner. Suppression of EAE was correlated with a significant decrease in the infiltration of monocytes, granulocytes, and natural killer cells, reduced demyelination, and downregulation of IL-1β, CCL2, and IFNγ gene expression in the spinal cord. These results underscore the therapeutic promise of concurrently targeting the TLR7 and NOD2 pathways in alleviating neuroinflammation associated with MS, paving the way for novel and more efficacious treatment strategies.
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