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Interleukin-9 protects from microglia- and TNF-mediated synaptotoxicity in experimental multiple sclerosis.
- Source :
-
Journal of neuroinflammation [J Neuroinflammation] 2024 May 14; Vol. 21 (1), pp. 128. Date of Electronic Publication: 2024 May 14. - Publication Year :
- 2024
-
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.<br />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.<br />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.<br />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.<br /> (© 2024. The Author(s).)
- Subjects :
- Animals
Mice
Disease Models, Animal
Membrane Glycoproteins metabolism
Multiple Sclerosis drug therapy
Multiple Sclerosis metabolism
Multiple Sclerosis pathology
Neurons metabolism
Neurons drug effects
Neurons pathology
Neuroprotective Agents pharmacology
Neuroprotective Agents therapeutic use
Encephalomyelitis, Autoimmune, Experimental metabolism
Encephalomyelitis, Autoimmune, Experimental pathology
Encephalomyelitis, Autoimmune, Experimental chemically induced
Interleukin-9 metabolism
Interleukin-9 pharmacology
Mice, Inbred C57BL
Microglia metabolism
Microglia drug effects
Microglia pathology
Synapses drug effects
Synapses metabolism
Synapses pathology
Tumor Necrosis Factor-alpha metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1742-2094
- Volume :
- 21
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of neuroinflammation
- Publication Type :
- Academic Journal
- Accession number :
- 38745307
- Full Text :
- https://doi.org/10.1186/s12974-024-03120-9