Background Multiple sclerosis (MS) is a progressive neurodegenerative disease of the central nervous system characterized by inflammation-driven synaptic abnormalities. Interleukin-9 (IL-9) is emerging as a pleiotropic cytokine involved in MS pathophysiology.Methods Through biochemical, immunohistochemical, and electrophysiological experiments, we investigated the effects of both peripheral and central administration of IL-9 on C57/BL6 female mice with experimental autoimmune encephalomyelitis (EAE), a model of MS.Results We demonstrated that both systemic and local administration of IL-9 significantly improved clinical disability, reduced neuroinflammation, and mitigated synaptic damage in EAE. The results unveil an unrecognized central effect of IL-9 against microglia- and TNF-mediated neuronal excitotoxicity. Two main mechanisms emerged: first, IL-9 modulated microglial inflammatory activity by enhancing the expression of the triggering receptor expressed on myeloid cells-2 (TREM2) and reducing TNF release. Second, IL-9 suppressed neuronal TNF signaling, thereby blocking its synaptotoxic effects.Conclusions The data presented in this work highlight IL-9 as a critical neuroprotective molecule capable of interfering with inflammatory synaptopathy in EAE. These findings open new avenues for treatments targeting the neurodegenerative damage associated with MS, as well as other inflammatory and neurodegenerative disorders of the central nervous system.

Guadalupi, L., Vanni, V., Balletta, S., Caioli, S., De Vito, F., Fresegna, D., et al. (2024). Interleukin-9 protects from microglia- and TNF-mediated synaptotoxicity in experimental multiple sclerosis. JOURNAL OF NEUROINFLAMMATION, 21(1), 1-16 [10.1186/s12974-024-03120-9].

Interleukin-9 protects from microglia- and TNF-mediated synaptotoxicity in experimental multiple sclerosis

Guadalupi, Livia;Vanni, Valentina;Balletta, Sara;Caioli, Silvia;De Vito, Francesca;Fresegna, Diego;Sanna, Krizia;Volpe, Elisabetta;Stampanoni Bassi, Mario;Gilio, Luana;Dolcetti, Ettore;Buttari, Fabio;Centonze, Diego;Musella, Alessandra
2024-05-14

Abstract

Background Multiple sclerosis (MS) is a progressive neurodegenerative disease of the central nervous system characterized by inflammation-driven synaptic abnormalities. Interleukin-9 (IL-9) is emerging as a pleiotropic cytokine involved in MS pathophysiology.Methods Through biochemical, immunohistochemical, and electrophysiological experiments, we investigated the effects of both peripheral and central administration of IL-9 on C57/BL6 female mice with experimental autoimmune encephalomyelitis (EAE), a model of MS.Results We demonstrated that both systemic and local administration of IL-9 significantly improved clinical disability, reduced neuroinflammation, and mitigated synaptic damage in EAE. The results unveil an unrecognized central effect of IL-9 against microglia- and TNF-mediated neuronal excitotoxicity. Two main mechanisms emerged: first, IL-9 modulated microglial inflammatory activity by enhancing the expression of the triggering receptor expressed on myeloid cells-2 (TREM2) and reducing TNF release. Second, IL-9 suppressed neuronal TNF signaling, thereby blocking its synaptotoxic effects.Conclusions The data presented in this work highlight IL-9 as a critical neuroprotective molecule capable of interfering with inflammatory synaptopathy in EAE. These findings open new avenues for treatments targeting the neurodegenerative damage associated with MS, as well as other inflammatory and neurodegenerative disorders of the central nervous system.
14-mag-2024
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/26
Settore MEDS-02/C - Storia della medicina
English
Experimental multiple sclerosis
Glutamate transmission
Inflammatory cytokines
Microglia activation
Neuroinflammation
Synaptopathy
Guadalupi, L., Vanni, V., Balletta, S., Caioli, S., De Vito, F., Fresegna, D., et al. (2024). Interleukin-9 protects from microglia- and TNF-mediated synaptotoxicity in experimental multiple sclerosis. JOURNAL OF NEUROINFLAMMATION, 21(1), 1-16 [10.1186/s12974-024-03120-9].
Guadalupi, L; Vanni, V; Balletta, S; Caioli, S; De Vito, F; Fresegna, D; Sanna, K; Nencini, M; Donninelli, G; Volpe, E; Mariani, F; Battistini, L; Sta...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/389554
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