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

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.Aim: In this study, we demonstrated that both peripheral and central administration of IL-9 significantly improved clinical disability, reduced neuroinflammation, and mitigated synaptic damage in experimental autoimmune encephalomyelitis (EAE).Results: Biochemical, immunohistochemical, and electrophysiological experiments unmasked previously unrecognized central effects of IL-9 against microglia- and TNF-mediated neuronal excitotoxicity. Two main mechanisms emerged: first, IL-9 modulated microglial inflammatory activity, 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 able to interfere with inflammatory synaptopathy in EAE, opening new avenues for treatments targeting the neurodegenerative damage associated with MS, and other inflammatory and neurodegenerative disorders of the central nervous system.