Fumarates modulate microglia activation through a novel HCAR2 signaling pathway and rescue synaptic dysregulation in inflamed CNS

Abstract Dimethyl fumarate (DMF), recently approved as an oral immunomodulatory treatment for relapsing-remitting multiple sclerosis (MS), metabolizes to monomethyl fumarate (MMF) which crosses the blood–brain barrier and has demonstrated neuroprotective effects in experimental studies. We postulated that MMF exerts neuroprotective effects through modulation of microglia activation, a critical component of the neuroinflammatory cascade that occurs in neurodegenerative diseases such as MS. To ascertain our hypothesis and define the mechanistic pathways involved in the modulating effect of fumarates, we used real-time PCR and biochemical assays to assess changes in the molecular and functional phenotype of microglia, quantitative Western blotting to monitor activation of postulated pathway components, and ex vivo whole-cell patch clamp recording of excitatory post-synaptic currents in corticostriatal slices from mice with experimental autoimmune encephalomyelitis (EAE), a model for MS, to study synaptic transmission. We show that exposure to MMF switches the molecular and functional phenotype of activated microglia from classically activated, pro-inflammatory type to alternatively activated, neuroprotective one, through activation of the hydroxycarboxylic acid receptor 2 (HCAR2). We validate a downstream pathway mediated through the AMPK–Sirt1 axis resulting in deacetylation, and thereby inhibition, of NF-κB and, consequently, of secretion of pro-infl...
Source: Acta Neuropathologica - Category: Neurology Source Type: research

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Leukocyte trafficking is a key event during autoimmune and inflammatory responses. The subarachnoid space (SAS) and cerebrospinal fluid are major routes for the migration of encephalitogenic T cells into the central nervous system (CNS) during experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis, and are sites of T cell activation before the invasion of CNS parenchyma. In particular, autoreactive Th1 and Th17 cell trafficking and reactivation in the CNS are required for the pathogenesis of EAE. However, the molecular mechanisms controlling T cell dynamics during EAE are unclear. We used t...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
Authors: Wang Y, Guo L, Wang J, Shi W, Xia Z, Li B Abstract Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by neuronal demyelination. MS pathogenesis occurs via multiple mechanisms, and is mediated in part by oligodendrocyte apoptosis and a robust inflammatory response. In the present study, Necrostatin-1 (Nec-1), a specific inhibitor of the receptor-interacting protein 1 kinase domain, was revealed to effectively alleviate the severity and pathological damage associated with experimental autoimmune encephalomyelitis (EAE), a commonly used mouse model of MS. In addition...
Source: Experimental and Therapeutic Medicine - Category: General Medicine Tags: Exp Ther Med Source Type: research
ConclusionsClinicians should be aware to early recognize acute and subacute respiratory adverse events for a promptly management. In these patients re-treatment is challenging.
Source: Multiple Sclerosis and Related Disorders - Category: Neurology Source Type: research
Abstract Multiple sclerosis (MS) is a chronic, inflammatory, neurodegenerative disease with an autoimmune component. It was suggested that potassium channels, which are involved in crucial biological functions may have a role in different diseases, including MS and its animal model, experimental autoimmune encephalomyelitis (EAE). It was shown that voltage-gated potassium channels Kv1.5 are responsible for fine-tuning in the immune physiology and influence proliferation and differentiation in microglia and astrocytes. Here, we explored the cellular distribution of the Kv1.5 channel, together with its transcript an...
Source: Neurochemical Research - Category: Neuroscience Authors: Tags: Neurochem Res Source Type: research
Kamila Migacz-Gruszka, Wojciech Branicki, Aleksander Obtulowicz, Magdalena Pirowska, Krystian Gruszka, Anna Wojas-PelcInternational Journal of Trichology 2019 11(5):185-188 The term “microbiome” defines the collective genome of all commensal, symbiotic, and pathogenic microbes living in the human body. The composition of microbiota in the gut and skin is influenced by many factors such as the stage of life, nutrition, lifestyle, and gender. In the past few years, several scientific papers have demonstrated an implication of microbiota in many immune-mediated diseases, for example, diabetes, ulcerative colitis,...
Source: International Journal of Trichology - Category: Dermatology Authors: Source Type: research
ConclusionsVidofludimus demonstrated a positive safety profile, making it a promising candidate for the treatment of a variety of immune-related diseases.Trial RegistrationsClinicalTrials.gov identifier: NCT01010581.
Source: Drugs in R&D - Category: Drugs & Pharmacology Source Type: research
ConclusionThis case demonstrated a favorable outcome in administering rituximab for NMOSD with disease onset during pregnancy. This description of therapy for disease onset during pregnancy is novel, and adds to the few existing case reports of administering rituximab during pregnancy.
Source: Multiple Sclerosis and Related Disorders - Category: Neurology Source Type: research
AbstractAryl hydrocarbon receptor (AhR), a type of transcriptional factor, is widely expressed in immune cells. The activation of AhR signaling pathway depends on its ligands, which exist in environment and can also be produced by metabolism. Normal expressions of AhR and AhR-mediated signaling may be essential for immune responses, and effects of AhR signaling on the development and function of innate and adaptive immune cells have also been revealed in previous studies. Recent studies also indicate that aberrant AhR signaling may be related to autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus eryth...
Source: Inflammopharmacology - Category: Drugs & Pharmacology Source Type: research
Publication date: Available online 10 October 2019Source: Life SciencesAuthor(s): Yam Nath Paudel, Efthalia Angelopoulou, Bhuvan K. C, Christina Piperi, Iekhsan OthmanAbstractMultiple sclerosis (MS) is an autoimmune chronic inflammatory disease with distinctive features of focal demyelination, axonal loss, activation of glial cells, and immune cells infiltration. The precise molecular mechanism underlying the disease progression remains enigmatic despite of the rapid progression on experimental and clinical MS research. The focus of MS therapy relies on the repression of the pathogenic autoimmune response without compromis...
Source: Life Sciences - Category: Biology Source Type: research
ConclusionsThis study is first to demonstrate that X-chromosome-linked IRAK1 polymorphisms are associated with the risk of NMOSD and provide novel insights into the underlying mechanisms of this disease. Further studies are needed to elucidate the function of IRAK1 variants in the pathogenesis of NMOSD and the underlying molecular mechanisms.
Source: Multiple Sclerosis and Related Disorders - Category: Neurology Source Type: research
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