NLRX1 inhibits the early stages of CNS inflammation and prevents the onset of spontaneous autoimmunity

by Marjan Gharagozloo, Shaimaa Mahmoud, Camille Simard, Kenzo Yamamoto, Diwakar Bobbala, Subburaj Ilangumaran, Matthew D. Smith, Albert Lamontagne, Samir Jarjoura, Jean-Bernard Denault, V éronique Blais, Louis Gendron, Carles Vilariño-Güell, A. Dessa Sadovnick, Jenny P. Ting, Peter A. Calabresi, Abdelaziz Amrani, Denis Gris Nucleotide-binding, leucine-rich repeat containing X1 (NLRX1) is a mitochondria-located innate immune sensor that inhibits major pro-inflammatory pathways such as type I interferon and nuclear factor-κB signaling. We generated a novel, spontaneous, and rapidly progressing mouse model of multiple sclerosis (MS) by crossing myelin-specific T-cell receptor (TCR) transgenic mice withNlrx1−/− mice. About half of the resulting progeny developed spontaneous experimental autoimmune encephalomyelitis (spEAE), which was associated with severe demyelination and inflammation in the central nervous system (CNS). Using lymphocyte-deficient mice and a series of adoptive transfer experiments, we demonstrate that genetic susceptibility to EAE lies within the innate immune compartment. We show that NLRX1 inhibits the subclinical stages of microglial activation and prevents the generation of neurotoxic astrocytes that induce neuronal and oligodendrocyte death in vitro. Moreover, we discovered several mutations withinNLRX1 that run in MS-affected families. In summary, our findings highlight the importance of NLRX1 in controlling the early...
Source: PLoS Biology: Archived Table of Contents - Category: Biology Authors: Source Type: research

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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
Publication date: Available online 15 October 2019Source: Multiple Sclerosis and Related DisordersAuthor(s): Paula Wildner, Mariusz StasioĊ‚ek, Mariola MatysiakAbstractMultiple sclerosis (MS) is the most common acquired demyelinating disorder of the central nervous system (CNS). Diagnosing MS can be very challenging owing to its variable clinical features and lack of specific tests. Magnetic resonance imaging (MRI) is a key measure in this process. Although white matter lesions on brain MRI are regarded as a hallmark of MS, they are a common radiological finding and their pattern may overlap in particular CNS inflammatory ...
Source: Multiple Sclerosis and Related Disorders - Category: Neurology 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
A new study examining the role that star-shaped brain cells called astrocytes play in Huntington ’s disease has identified a potential strategy that may halt the disease and repair some of the damage it causes.Astrocytes interact with and support neurons, or nerve cells, and other brain cells. Although astrocytes outnumber neurons, little is known about how they interact with synapses, the junctions between neurons that enable them to communicate and convey messages to each other.The study, led by UCLA researchers and published in the journal Science Translational Medicine, found that Huntington ’s disease dama...
Source: UCLA Newsroom: Health Sciences - Category: Universities & Medical Training Source Type: news
In this study, we provide in vivo evidence that this spatial specificity is lost in Shiverer (Shi) mice, a model for progressive multiple sclerosis (MS), resulting in inappropriate intrusion of SNPH into dendrites of cerebellar Purkinje cells with neurodegenerative consequences. Thus, reconstituting dendritic SNPH intrusion in SNPH-KO mice by viral transduction greatly sensitizes Purkinje cells to excitotoxicity when the glutamatergic climbing fibers are stimulated. Finally, we demonstrate in vitro that overexpression of SNPH in dendrites compromises neuronal viability by inducing N-methyl-D-aspartate (NMDA) exci...
Source: Cell Reports - Category: Cytology Source Type: research
Publication date: Available online 15 October 2019Source: Advances in Biological RegulationAuthor(s): Sandeep K. Singh, Sarah SpiegelAbstractTriple-negative breast cancer (TNBC) is very aggressive with high metastatic and mortality rates and unfortunately, except for chemotherapy, there are few therapeutic options. The bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P) regulates numerous processes important for cancer progression, metastasis, and neuropathic pain. The pro-drug FTY720 (fingolimod, Gilenya) used to treat multiple sclerosis is phosphorylated in the body to a S1P mimic that binds to S1PRs, except ...
Source: Advances in Biological Regulation - Category: Biology Source Type: research
CONCLUSION: Voiders and VD patients showed distinctly different FC in their Voiding Initiation Network. Machine-learning is able to identify brain centers contributing to these observed differences. Knowledge of these centers and their connectivity may allow phenotyping patients to centrally focused treatments such as cortical modulation. PMID: 31607098 [PubMed]
Source: International Neurourology Journal - Category: Urology & Nephrology Tags: Int Neurourol J Source Type: research
Genes &Immunity, Published online: 16 October 2019; doi:10.1038/s41435-019-0089-5Transcribed B lymphocyte genes and multiple sclerosis risk genes are underrepresented in Epstein–Barr Virus hypomethylated regions
Source: Genes and Immunity - Category: Genetics & Stem Cells Authors: 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
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