A Gentile1,2, F De Vito3, D Fresegna2, F R Rizzo1, S Bullitta1,2, L Guadalupi1,2, V Vanni2, F Buttari3, M Stampanoni Bassi3, A Leuti4,5, V Chiurchiù4,5, G A Marfia6, G Mandolesi7, D Centonze1,3, A Musella7. 1. Synaptic Immunopathology Lab, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy. 2. Synaptic Immunopathology Lab, IRCCS San Raffaele, Rome, Italy. 3. Unit of Neurology, IRCCS Neuromed, Pozzilli, Italy. 4. Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy. 5. European Center for Brain Research (CERC)/IRCCS Fondazione Santa Lucia, Rome, Italy. 6. Multiple Sclerosis Research Unit, Department of Systems Medicine, Tor Vergata University, Rome, Italy. 7. Synaptic Immunopathology Lab, IRCCS San Raffaele Pisana and University San Raffaele, Rome, Italy.
Abstract
AIMS: The crucial step in the pathogenic events that lead to the development and the progression of multiple sclerosis (MS) is the infiltration of autoreactive T cells in the brain. Data from experimental autoimmune encephalomyelitis (EAE) mice indicate that, together with microglia, T cells are responsible for the enhancement of the glutamatergic transmission in central neurons, contributing to glutamate-mediated excitotoxicity, a pathological hallmark of both EAE and MS brains. Here, we addressed the synaptic role of T cells taken from MS patients. METHODS: A chimeric model of human T cells and murine brain slices was established to record, by Patch Clamp technique, the glutamatergic transmission in the presence of T cells isolated from the peripheral blood of healthy subjects (HS), active (a) and nonactive (na) relapsing remitting MS patients. Intracellular staining and flow cytometry were used to assess tumour necrosis factor (TNF) expression in T cells. RESULTS: Chimeric experiments indicated that, compared to HS and naMS, T cells from aMS induced an increase in glutamatergic kinetic properties of striatal neurons. Such alteration, reminiscent of the those induced by EAE T cells, was blocked by incubation of the slices with etanercept, a TNF receptor antagonist. Of note, T cells from aMS expressed more TNF than naMS patients and HS subjects. CONCLUSION: These data highlight the synaptotoxic potential retained by MS T cells, suggesting that during the inflammatory phase of the disease infiltrating T cells could influence the neuronal activity contributing to the TNF-mediated mechanisms of glutamate excitotoxicity in central neurons.
AIMS: The crucial step in the pathogenic events that lead to the development and the progression of multiple sclerosis (MS) is the infiltration of autoreactive T cells in the brain. Data from experimental autoimmune encephalomyelitis (EAE) mice indicate that, together with microglia, T cells are responsible for the enhancement of the glutamatergic transmission in central neurons, contributing to glutamate-mediated excitotoxicity, a pathological hallmark of both EAE and MS brains. Here, we addressed the synaptic role of T cells taken from MSpatients. METHODS: A chimeric model of human T cells and murine brain slices was established to record, by Patch Clamp technique, the glutamatergic transmission in the presence of T cells isolated from the peripheral blood of healthy subjects (HS), active (a) and nonactive (na) relapsing remitting MSpatients. Intracellular staining and flow cytometry were used to assess tumour necrosis factor (TNF) expression in T cells. RESULTS: Chimeric experiments indicated that, compared to HS and naMS, T cells from aMS induced an increase in glutamatergic kinetic properties of striatal neurons. Such alteration, reminiscent of the those induced by EAE T cells, was blocked by incubation of the slices with etanercept, a TNF receptor antagonist. Of note, T cells from aMS expressed more TNF than naMS patients and HS subjects. CONCLUSION: These data highlight the synaptotoxic potential retained by MS T cells, suggesting that during the inflammatory phase of the disease infiltrating T cells could influence the neuronal activity contributing to the TNF-mediated mechanisms of glutamate excitotoxicity in central neurons.
Authors: Mario Stampanoni Bassi; Fabio Buttari; Luana Gilio; Nicla De Paolis; Diego Fresegna; Diego Centonze; Ennio Iezzi Journal: Front Neurol Date: 2020-07-07 Impact factor: 4.003
Authors: Claudio Derada Troletti; Gaby Enzmann; Valerio Chiurchiù; Alwin Kamermans; Silvia Martina Tietz; Paul C Norris; Neda Haghayegh Jahromi; Alessandro Leuti; Susanne M A van der Pol; Marijn Schouten; Charles N Serhan; Helga E de Vries; Britta Engelhardt; Gijs Kooij Journal: Cell Rep Date: 2021-06-01 Impact factor: 9.423