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Interleukin-9 protects from microglia- and TNF-mediated synaptotoxicity in experimental multiple sclerosis
Livia Guadalupi1,2, Valentina Vanni2, Sara Balletta3
1Department of Systems Medicine, University of Rome Tor Vergata, Rome, 00133, Italy.
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.
Insights
Interleukin-9 (IL-9) administration improved multiple sclerosis (MS) symptoms in mice by reducing neuroinflammation and synaptic damage. This cytokine shows potential as a neuroprotective therapy for MS and other central nervous system disorders.
Area of Science:
- Neuroimmunology
- Neuroinflammation
- Cytokine Signaling
Background:
- Multiple sclerosis (MS) is a neurodegenerative disease characterized by inflammation-induced synaptic abnormalities.
- Interleukin-9 (IL-9) is a cytokine implicated in the pathophysiology of MS.
Purpose of the Study:
- To investigate the therapeutic effects of Interleukin-9 (IL-9) in a mouse model of Multiple Sclerosis (MS).
- To elucidate the mechanisms underlying IL-9's neuroprotective actions in experimental autoimmune encephalomyelitis (EAE).
Main Methods:
- Biochemical, immunohistochemical, and electrophysiological analyses were performed.
- IL-9 was administered both peripherally and centrally to C57/BL6 female mice with EAE.
- Effects on clinical disability, neuroinflammation, and synaptic damage were assessed.
Main Results:
- Systemic and local IL-9 administration significantly improved clinical outcomes and reduced neuroinflammation and synaptic damage in EAE mice.
- IL-9 demonstrated a central neuroprotective effect against microglia- and TNF-mediated excitotoxicity.
- IL-9 enhanced TREM2 expression, reduced microglial TNF release, and suppressed neuronal TNF signaling.
Conclusions:
- IL-9 acts as a critical neuroprotective molecule against inflammatory synaptopathy in EAE.
- Findings suggest IL-9 as a potential therapeutic target for MS and other neurodegenerative diseases.
- IL-9's ability to modulate microglial activity and neuronal signaling offers new treatment avenues.
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