myelin-oligodendrocyte-glycoprotein-(35-55) and Neurogenic-Inflammation

Pathologic roles of innate immunity in neurologic disorders are well described, but their beneficial aspects are less understood. Dectin-1, a C-type lectin receptor (CLR), is largely known to induce inflammation. Here, we report that Dectin-1 limited experimental autoimmune encephalomyelitis (EAE), while its downstream signaling molecule, Card9, promoted the disease. Myeloid cells mediated the pro-resolution function of Dectin-1 in EAE with enhanced gene expression of the neuroprotective molecule, Oncostatin M (Osm), through a Card9-independent pathway, mediated by the transcription factor NFAT. Furthermore, we find that the Osm receptor (OsmR) functioned specifically in astrocytes to reduce EAE severity. Notably, Dectin-1 did not respond to heat-killed Mycobacteria, an adjuvant to induce EAE. Instead, endogenous Dectin-1 ligands, including galectin-9, in the central nervous system (CNS) were involved to limit EAE. Our study reveals a mechanism of beneficial myeloid cell-astrocyte crosstalk regulated by a Dectin-1 pathway and identifies potential therapeutic targets for autoimmune neuroinflammation.

Topics: Animals; Astrocytes; Brain; CARD Signaling Adaptor Proteins; Cell Communication; Cells, Cultured; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Galectins; Gene Expression Regulation; Lectins, C-Type; Mice, Inbred C57BL; Mice, Knockout; Multiple Sclerosis; Myelin-Oligodendrocyte Glycoprotein; Myeloid Cells; Neurogenic Inflammation; Oncostatin M; Oncostatin M Receptor beta Subunit; Peptide Fragments; Receptors, Mitogen; Signal Transduction

Increasing evidence points to an important role for neutrophils in participating in the pathogenesis of the human demyelinating disease MS and the animal model EAE. Therefore, a better understanding of the signals controlling migration of neutrophils as well as evaluating the role of these cells in demyelination is important to define cellular components that contribute to disease in MS patients. In this study, we examined the functional role of the chemokine CXCL1 in contributing to neuroinflammation and demyelination in EAE. Using transgenic mice in which expression of CXCL1 is under the control of a tetracycline-inducible promoter active within glial fibrillary acidic protein-positive cells, we have shown that sustained CXCL1 expression within the CNS increased the severity of clinical and histologic disease that was independent of an increase in the frequency of encephalitogenic Th1 and Th17 cells. Rather, disease was associated with enhanced recruitment of CD11b

Topics: Animals; Autoantigens; CD11b Antigen; Cells, Cultured; Central Nervous System; Chemokine CXCL1; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Gene Expression Regulation; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Targeted Therapy; Multiple Sclerosis; Myelin-Oligodendrocyte Glycoprotein; Neurogenic Inflammation; Neutrophil Infiltration; Neutrophils; Peptide Fragments; Signal Transduction; Spinal Cord

Genes and pathways in which inactivation dampens tissue inflammation present new opportunities for understanding the pathogenesis of common human inflammatory diseases, including inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis. We identified a mutation in the gene encoding the deubiquitination enzyme USP15 (Usp15

Topics: Animals; DNA-Binding Proteins; Encephalomyelitis, Autoimmune, Experimental; HEK293 Cells; Humans; Immunity, Innate; Interferon Type I; Malaria, Cerebral; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Transgenic; Molecular Targeted Therapy; Myelin-Oligodendrocyte Glycoprotein; Neurogenic Inflammation; Peptide Fragments; Plasmodium berghei; Transcription Factors; Ubiquitin-Specific Proteases