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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2024

Open Access 01-12-2024 | Multiple Sclerosis | Research

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

Authors: Livia Guadalupi, Valentina Vanni, Sara Balletta, Silvia Caioli, Francesca De Vito, Diego Fresegna, Krizia Sanna, Monica Nencini, Gloria Donninelli, Elisabetta Volpe, Fabrizio Mariani, Luca Battistini, Mario Stampanoni Bassi, Luana Gilio, Antonio Bruno, Ettore Dolcetti, Fabio Buttari, Georgia Mandolesi, Diego Centonze, Alessandra Musella

Published in: Journal of Neuroinflammation | Issue 1/2024

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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.
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Metadata
Title
Interleukin-9 protects from microglia- and TNF-mediated synaptotoxicity in experimental multiple sclerosis
Authors
Livia Guadalupi
Valentina Vanni
Sara Balletta
Silvia Caioli
Francesca De Vito
Diego Fresegna
Krizia Sanna
Monica Nencini
Gloria Donninelli
Elisabetta Volpe
Fabrizio Mariani
Luca Battistini
Mario Stampanoni Bassi
Luana Gilio
Antonio Bruno
Ettore Dolcetti
Fabio Buttari
Georgia Mandolesi
Diego Centonze
Alessandra Musella
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2024
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-024-03120-9

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