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

期刊论文
出版模式：

开放获取
发表日期：

2024年5月14日

查看全文

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

摘要

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.