Interleukin-9 protects from microglia- and TNF-mediated synaptotoxicity in experimental multiple sclerosis.
Animals
Encephalomyelitis, Autoimmune, Experimental
/ metabolism
Mice
Microglia
/ metabolism
Mice, Inbred C57BL
Interleukin-9
/ metabolism
Female
Tumor Necrosis Factor-alpha
/ metabolism
Synapses
/ drug effects
Neuroprotective Agents
/ pharmacology
Membrane Glycoproteins
/ metabolism
Neurons
/ metabolism
Multiple Sclerosis
/ pathology
Disease Models, Animal
Experimental multiple sclerosis
Glutamate transmission
Inflammatory cytokines
Microglia activation
Neuroinflammation
Synaptopathy
Journal
Journal of neuroinflammation
ISSN: 1742-2094
Titre abrégé: J Neuroinflammation
Pays: England
ID NLM: 101222974
Informations de publication
Date de publication:
14 May 2024
14 May 2024
Historique:
received:
09
02
2024
accepted:
01
05
2024
medline:
15
5
2024
pubmed:
15
5
2024
entrez:
14
5
2024
Statut:
epublish
Résumé
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. 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. 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. 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.
Sections du résumé
BACKGROUND
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
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
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
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.
Identifiants
pubmed: 38745307
doi: 10.1186/s12974-024-03120-9
pii: 10.1186/s12974-024-03120-9
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
128Subventions
Organisme : Fondazione Italiana Sclerosi Multipla
ID : and co-financed with the '5 per mille' public funding, research fellowship 2020/BS/003
Organisme : Fondazione Italiana Sclerosi Multipla
ID : FISM2016/R/31
Organisme : Ministero della Salute
ID : GR-2016-02361163
Organisme : Ministero della Salute
ID : Progetto Ricerca Corrente to IRCCS San Raffaele;
Organisme : Ministero della Salute
ID : Progetto Ricerca Corrente to IRCCS Neuromed
Organisme : Ministero della Salute
ID : GR-2016-02361163
Organisme : Ministry of University and Research and the European Union - Next Generation EU - National Recovery and Resilience Plan (NRRP)
ID : MNESYS (PE0000006)
Organisme : CNR FOE 2020 and 2021
ID : project 'Nuovi Biomarker Diagnostici e Terapeutici delle Malattie Neurodegenerative
Organisme : CNR FOE 2020 and 2021
ID : project 'Nuovi Biomarker Diagnostici e Terapeutici delle Malattie Neurodegenerative
Organisme : Private donation
ID : In memory of Veronica Tozzi to DC
Informations de copyright
© 2024. The Author(s).
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