Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Experimental autoimmune encephalomyelitis (EAE) is an autoimmune demyelinating disease commonly used to model the pathogenetic mechanisms involved in multiple sclerosis (MS). In this study, we examined the effects of immunization with the myelin oligodendrocyte glycoprotein MOG(35-55) on the expression of molecules of the innate immune system, namely toll-like receptor 2 (TLR2) and CD14. Expression of the mRNA encoding TLR2 increased in the choroid plexus, the leptomeninges and within few isolated cells in the CNS parenchyma 4 to 8 days after immunization with MOG. At day 10, the signal spread across the meninges, few perivascular regions and over isolated groups of parenchymal cells. Three weeks after the MOG treatment, at which time animals showed severe clinical symptoms, a robust expression of both TLR2 and CD14 transcripts occurred in barrier-associated structures, as well as parenchymal elements of the spinal cord, and within numerous regions of the brain including, the medulla, cerebellum and the cortex. Dual labeling provided the anatomical evidence that microglia/macrophages were positive for TLR2 in the brain of EAE mice. The regions that exhibited chronic expression of TLR2 and CD14 were also associated with an increase in NF-kappaB activity and transcriptional activation of genes encoding numerous proinflammatory molecules. The present data provide evidence that receptors of the pathogen-associated molecular patterns are strongly induced in the CNS of EAE mice, further reinforcing the concept that the innate immune system plays a determinant role in this autoimmune demyelinating disease.
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PMID:The clinical course of experimental autoimmune encephalomyelitis is associated with a profound and sustained transcriptional activation of the genes encoding toll-like receptor 2 and CD14 in the mouse CNS. 1214 99

Peripheral peptidolgycan (PGN) is present within antigen-presenting cells in the central nervous system (CNS) of multiple sclerosis (MS) patients, possibly playing a role in neuroinflammation. Accordingly, PGN is linked with disease progression in the animal model of MS, experimental autoimmune encephalomyelitis (EAE), but the role of specific PGN-sensing proteins is unknown. Here we report that the progression of EAE was dependent on the intracellular PGN sensors NOD1 and NOD2 and their common downstream adaptor molecule, receptor interacting protein 2 (RIP2; also known as RIPK2 and RICK). We found that RIP2, but not toll-like receptor 2 (TLR2), played a critical role in the activation of CNS-infiltrating dendritic cells. Our results suggest that PGN in the CNS is involved in the pathogenesis of EAE through the activation of infiltrating dendritic cells via NOD1-, NOD2-, and RIP2-mediated pathways.
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PMID:Signaling via the RIP2 adaptor protein in central nervous system-infiltrating dendritic cells promotes inflammation and autoimmunity. 2146 91

The death of mature oligodendrocytes (OLs) leads to demyelination in the central nervous system (CNS) and subsequently to functional deficits. Remyelination requires the differentiation of oligodendrocyte progenitor cells (OPCs) into myelinating OLs, which in the CNS with neurodegenerative diseases such as multiple sclerosis (MS), is often inhibited. Among the inhibitors of OPC differentiation are toll-like receptor 2 (TLR2) and interleukin-1 receptor-associated kinase 1 (IRAK1) signaling, and both are negatively regulated by microRNA-146a (miR-146a). Therefore, we hypothesized that increase of miR-146a level in the CNS would foster OPC differentiation and remyelination by inhibiting the TLR2/IRAK1 signaling pathway. Here, we tested this hypothesis using exogenous miR-146a mimics and a mouse model of MS, experimental autoimmune encephalomyelitis (EAE) induced by immunization with myelin proteolipid protein peptide (PLP139-151). EAE mice were treated by miR-146a mimics or miR-146a mimic negative controls, respectively, which initiated at day 14 post immunization, once a week for 6 consecutive weeks. Neurological function was monitored daily. Immunofluorescent staining, qRT-PCR and Western blot were used to measure the differentiation of OPCs and myelination, and to investigate the underlying mechanisms of action of miR-146a. Using a fluorescence tracing approach, we found that miR-146a mimics crossed the blood brain barrier and targeted OPCs and microglia/macrophages after systemic administration. MiR-146a mimic treatment substantially improved neurological functional outcome, increased the number of newly generated OLs which may facilitate remyelination in the CNS. The cell number, cytokine level and protein levels of M2 phonotype of microglia/macrophages significantly increased, while cytokine and protein levels of the M1 phenotype significantly decreased after miR-146a mimic treatment. Increased OPC differentiation and remyelination were associated with reduction of TLR2/IRAK1 signaling pathway activity by miR-146a mimic treatment. This study provides insight into the cellular and molecular bases for the therapeutic effects of miR-146a on OPC differentiation and remyelination, and suggests the potential of enhancing miR-146a as a treatment of demyelinating disorders.
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PMID:MiR-146a promotes oligodendrocyte progenitor cell differentiation and enhances remyelination in a model of experimental autoimmune encephalomyelitis. 3070 40