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OBJECTIVE: The frequency of inflammatory episodes in the early stages of multiple sclerosis (MS) has been correlated with late neurodegeneration, but the mechanism by which inflammation gives rise to delayed neuronal damage is unknown. Increased activity of the neurotransmitter glutamate is thought to play a role in the inflammation-driven neurodegenerative process of MS, and therefore we tested whether inflammatory cytokines released during acute MS attacks have the property of enhancing glutamate-mediated transmission and excitotoxicity in central neurons. METHODS: We compared the effect of cerebrospinal fluid (CSF) from active and quiescent MS patients on glutamate-mediated excitatory postsynaptic currents (EPSCs) and excitotoxic damage in rodent brain slices. We also measured CSF concentrations of tumor necrosis factor-[alpha], of interleukin-1[beta] (IL-1[beta]), and of IL-1 receptor antagonist (IL-1ra), and correlated cytokine levels with cortical excitability assessed in MS patients by means of paired-pulse transcranial magnetic stimulation (TMS). RESULTS: CSF from MS patients with enhanced brain lesions at magnetic resonance imaging was able to increase spontaneous EPSC frequency and glutamate-mediated neuronal swelling in vitro, through a mechanism dependent on enhanced IL-1[beta] signaling and increased glutamate [alpha]-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor stimulation. Furthermore, IL-1[beta]/IL-1ra ratio was significantly higher in the CSF of active MS subjects, and correlated with intracortical facilitation, an accredited TMS measure of glutamate transmission. Finally, we identified for the first time transient receptor potential vanilloid 1 channels as essential intermediates for the synaptic action of IL-1[beta] on central glutamatergic synapses. INTERPRETATION: Our results provide compelling evidence of the synaptic mechanism linking inflammation and excitotoxic neurodegeneration in MS. ANN NEUROL 2012;71:76-83. [ABSTRACT FROM AUTHOR]

Gammadelta T lymphocytes are thought to be involved in multiple sclerosis (MS) pathogenesis. In this work, we discuss the characteristics of these cells and possible implications in the pathogenesis of MS, focusing on the mechanism(s) underlying extravasation and tissue localization. Phenotype and transendothelial migration of γδ T cells from healthy donors and patients with relapsing–remitting MS were studied. In MS patients the Vδ2 T cell subset, expressing NKRP1A/CD161 adhesion molecule, is expanded and capable of transendothelial migration. Vδ1/Vδ2 subsets use distinct signal transduction pathways: Vδ1 cells lack NKRP1A and express PECAM-1/CD31, which drives transmigration, while Vδ2 cells are PECAM-1 negative and use NKRP1A. Vδ2 migration is coupled with CAMKII, whereas Vδ1 depend on PI-3K. NKRP1A and PECAM-1 selectively activate the two pathways: indeed, oligomerization of NKRP1A on Vδ2 T cells leads to CAMKII activation, occupancy of PECAM-1 on Vδ1 cells triggers the PI-3K-dependent Akt/PKB pathway. Moreover, Vδ2 T cells are CXCR3brightCXCR4dull, while Vδ1 are mostly CXCR4+. Vδ1 and Vδ2 cells transmigrate in response to IP-10/CXCL10 and SDF-1/CXCL12 according to the expression of their specific receptors. In a fraction of Vδ1 T cells coexpressing CXCR3 and CXCR4, the homeostatic chemokine 6Ckine/SLC/CCL21 is more effective. IP-10/CXCL10 or 6Ckine/SLC/CCL21 and SDF-1/CXCL12-induced transmigration is coupled to PI-3K/Akt/PKB, but only CXCR3 is capable of inducing CAMKII activation. We suggest that both subsets of γδ T lymphocytes may migrate to the site of lesion in MS using two different signaling pathways to extravasate and responding to different chemokines. [ABSTRACT FROM AUTHOR]

HDAC inhibitors (HDACi) exert beneficial effects in mdx mice, by promoting endogenous regeneration; however, the cellular determinants of HDACi activity on dystrophic muscles have not been determined. We show that fibroadipogenic progenitors (FAP) influence the regeneration potential of satellite cells during disease progression in mdx mice and mediate HDACi ability to selectively promote regeneration at early stages of disease. FAPs from young mdx mice promote, while FAPs from old mdx mice repress, satellite cell-mediated formation of myotubes. In young mdx mice HDACi inhibited FAP adipogenic potential, while enhancing their ability to promote differentiation of adjacent satellite cells, through upregulation of the soluble factor follistatin. By contrast, FAPs from old mdx mice were resistant to HDACi-mediated inhibition of adipogenesis and constitutively repressed satellite cell-mediated formation of myotubes. We show that transplantation of FAPs from regenerating young muscles restored HDACi ability to increase myofibre size in old mdx mice. These results reveal that FAPs are key cellular determinants of disease progression in mdx mice and mediate a previously unappreciated stage-specific beneficial effect of HDACi in dystrophic muscles., (Copyright © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.)