Abstract
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.
Highlights
Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS)
We have previously shown that simultaneous activation of innate receptors, Toll-like receptor (TLR) 9 and Nucleotide-binding oligomerization domain (NOD) 2 within the CNS via administration of experimental microparticle MIS416 had a protective effect in experimental autoimmune encephalomyelitis (EAE), an MS-like disease in mice, that resulted in suppression of disease activity (Khorooshi et al, 2020)
We investigated the effect of innate signaling in the CNS on demyelinating lesion pathology in a focal EAE mouse model
Summary
Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the CNS. Innate Signaling Suppresses Focal EAE demyelinating pathologies. We have extended these studies to evaluate the direct effect of innate signaling on demyelinating pathology by utilizing a focal EAE model. Focal EAE models described so far have used pro-inflammatory cytokines, such as tumor necrosis factor alpha, to induce cortical lesions in rodent brains (Merkler et al, 2006; Chaudhary et al, 2015; Lassmann and Bradl, 2017). We have innovated a novel focal EAE model that is induced in mice, without cytokines This approach allows for better understanding of the pathology with regards to cell infiltration, cytokine composition and general changes that occur in demyelinated lesions. In the present study we used this focal EAE model to show that innate receptor signaling within the CNS can prevent the formation of demyelinated lesions
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