MiR-142-3p is a Critical Modulator of TNF-mediated Neuronal Toxicity in Multiple Sclerosis

• Published in: Current neuropharmacology 2023-01, Vol.21 (12), p.2567-2582
• Main Authors: De Vito, Francesca, Balletta, Sara, Caioli, Silvia, Musella, Alessandra, Guadalupi, Livia, Vanni, Valentina, Fresegna, Diego, Bassi, Mario Stampanoni, Gilio, Luana, Sanna, Krizia, Gentile, Antonietta, Bruno, Antonio, Dolcetti, Ettore, Buttari, Fabio, Pavone, Luigi, Furlan, Roberto, Finardi, Annamaria, Perlas, Emerald, Hornstein, Eran, Centonze, Diego, Mandolesi, Georgia
• Format: Article
• Language: English
• Subjects: Animals; Antagomirs; Encephalomyelitis, Autoimmune, Experimental - genetics; Encephalomyelitis, Autoimmune, Experimental - pathology; Humans; Inflammation; Medicine, Neurology, Pharmacology, Neuroscience; Mice; MicroRNAs - genetics; Multiple Sclerosis
• ISSN: 1570-159X; 1875-6190
• DOI: 10.2174/1570159X21666230404103914

Background: TNF-dependent synaptotoxicity contributes to the neuronal damage occurring in patients with Multiple Sclerosis (pwMS) and its mouse model Experimental Autoimmune Encephalomyelitis (EAE). Here, we investigated miR-142-3p, a synaptotoxic microRNA induced by inflammation in EAE and MS, as a potential downstream effector of TNF signalling. Methods: Electrophysiological recordings, supported by molecular, biochemical and histochemical analyses, were performed to explore TNF-synaptotoxicity in the striatum of EAE and healthy mice. MiR-142 heterozygous (miR-142 HE) mice and/or LNA-anti miR-142-3p strategy were used to verify the TNF-miR-142-3p axis hypothesis. The cerebrospinal fluid (CSF) of 151 pwMS was analysed to evaluate possible correlation between TNF and miR-142-3p levels and their impact on clinical parameters (e.g. progression index (PI), age-related clinical severity (gARMSS)) and MRI measurements at diagnosis (T0). Results: High levels of TNF and miR-142-3p were detected in both EAE striatum and MS-CSF. The TNF-dependent glutamatergic alterations were prevented in the inflamed striatum of EAE miR-142 HE mice. Accordingly, TNF was ineffective in healthy striatal slices incubated with LNA-anti miR- 142-3p. However, both preclinical and clinical data did not validate the TNF-miR-142-3p axis hypothesis, suggesting a permissive neuronal role of miR-142-3p on TNF-signalling. Clinical data showed a negative impact of each molecule on disease course and/or brain lesions and unveiled that their high levels exert a detrimental synergistic effect on disease activity, PI and white matter lesion volume. Conclusion: We propose miR-142-3p as a critical modulator of TNF-mediated neuronal toxicity and suggest a detrimental synergistic action of these molecules on MS pathology.