Interleukin-17 affects synaptic plasticity and cognition in an experimental model of multiple sclerosis

• Published in: Cell reports (Cambridge) 2021-12, Vol.37 (10), p.110094-110094, Article 110094
• Main Authors: Di Filippo, Massimiliano, Mancini, Andrea, Bellingacci, Laura, Gaetani, Lorenzo, Mazzocchetti, Petra, Zelante, Teresa, La Barbera, Livia, De Luca, Antonella, Tantucci, Michela, Tozzi, Alessandro, Durante, Valentina, Sciaccaluga, Miriam, Megaro, Alfredo, Chiasserini, Davide, Salvadori, Nicola, Lisetti, Viviana, Portaccio, Emilio, Costa, Cinzia, Sarchielli, Paola, Amato, Maria Pia, Parnetti, Lucilla, Viscomi, Maria Teresa, Romani, Luigina, Calabresi, Paolo
• Format: Article
• Language: English
• Subjects: Animals; Behavior, Animal; CA1 Region, Hippocampal - metabolism; CA1 Region, Hippocampal - pathology; CA1 Region, Hippocampal - physiopathology; Cognition; cognitive impairment; Encephalomyelitis, Autoimmune, Experimental - metabolism; Encephalomyelitis, Autoimmune, Experimental - pathology; Encephalomyelitis, Autoimmune, Experimental - physiopathology; Encephalomyelitis, Autoimmune, Experimental - psychology; experimental autoimmune encephalomyelitis; hippocampus; inflammation; interleukin-17; Interleukin-17 - genetics; Interleukin-17 - metabolism; Long-Term Potentiation; Male; Mice; Mice, Biozzi; Mice, Inbred C57BL; Mice, Knockout; multiple sclerosis; neuroimmunology; Neuronal Plasticity; p38 Mitogen-Activated Protein Kinases; Receptors, Interleukin-17 - genetics; Receptors, Interleukin-17 - metabolism; Signal Transduction; Spatial Learning; Synapses - metabolism; Synapses - pathology; synaptic plasticity
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.110094

Cognitive impairment (CI) is a disabling concomitant of multiple sclerosis (MS) with a complex and controversial pathogenesis. The cytokine interleukin-17A (IL-17A) is involved in the immune pathogenesis of MS, but its possible effects on synaptic function and cognition are still largely unexplored. In this study, we show that the IL-17A receptor (IL-17RA) is highly expressed by hippocampal neurons in the CA1 area and that exposure to IL-17A dose-dependently disrupts hippocampal long-term potentiation (LTP) through the activation of its receptor and p38 mitogen-activated protein kinase (MAPK). During experimental autoimmune encephalomyelitis (EAE), IL-17A overexpression is paralleled by hippocampal LTP dysfunction. An in vivo behavioral analysis shows that visuo-spatial learning abilities are preserved when EAE is induced in mice lacking IL-17A. Overall, this study suggests a key role for the IL-17 axis in the neuro-immune cross-talk occurring in the hippocampal CA1 area and its potential involvement in synaptic dysfunction and MS-related CI. [Display omitted] •Hippocampal neurons express IL-17RA both under control conditions and during EAE•IL-17A dose-dependently blocks LTP via the activation of IL-17RA and p38 MAPK•Hippocampal IL-17A overexpression and synaptic dysfunction both occur during EAE•The lack of IL-17A ameliorates EAE-related cognitive deficits In this study, Di Filippo et al. investigate the pathogenesis of hippocampal synaptopathy in experimental autoimmune encephalomyelitis, highlighting an IL-17A-centered neuro-immune cross-talk. Besides its well-known immunopathogenic roles, the IL-17 axis might be directly involved in the modulation of synaptic plasticity and cognition, with potential therapeutic implications for people with multiple sclerosis.