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MiR-142-3p is a Critical Modulator of TNF-mediated Neuronal Toxicity in Multiple Sclerosis
Francesca De Vito1, Sara Balletta1,2, Silvia Caioli1
1Unit of Neurology, IRCCS Neuromed, Pozzilli, Isernia, Italy.
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.
Insights
Tumor necrosis factor (TNF) and miR-142-3p are linked to Multiple Sclerosis (MS) neuronal damage. While not directly causative, they synergistically worsen MS pathology and disease progression.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Tumor necrosis factor (TNF)-dependent synaptotoxicity contributes to neuronal damage in Multiple Sclerosis (MS) and its mouse model, Experimental Autoimmune Encephalomyelitis (EAE).
- MicroRNA-142-3p (miR-142-3p) is a synaptotoxic microRNA induced by inflammation in EAE and MS.
- This study investigated miR-142-3p as a potential downstream effector of TNF signaling in MS.
Purpose of the Study:
- To investigate the role of miR-142-3p in TNF-mediated synaptotoxicity in the context of Multiple Sclerosis.
- To determine if miR-142-3p acts as a downstream effector of TNF signaling in EAE and MS.
- To evaluate the correlation between TNF, miR-142-3p levels, and clinical/MRI parameters in patients with MS.
Main Methods:
- Electrophysiological recordings, molecular, biochemical, and histochemical analyses were used to study TNF-synaptotoxicity in EAE and healthy mice.
- miR-142 heterozygous mice and LNA-anti miR-142-3p strategies were employed to test the TNF-miR-142-3p axis hypothesis.
- Cerebrospinal fluid (CSF) from 151 patients with MS (pwMS) was analyzed for TNF and miR-142-3p levels and their correlation with clinical and MRI data.
Main Results:
- Elevated TNF and miR-142-3p levels were found in EAE striatum and MS-CSF.
- TNF-dependent glutamatergic alterations in EAE mice were prevented by miR-142 heterozygosity or anti-miR-142-3p treatment.
- Preclinical and clinical data did not validate the direct TNF-miR-142-3p axis but suggested a permissive role for miR-142-3p in TNF signaling. High levels of both molecules showed a detrimental synergistic effect on MS disease activity and lesions.
Conclusions:
- miR-142-3p is proposed as a critical modulator of TNF-mediated neuronal toxicity in MS.
- A detrimental synergistic action of TNF and miR-142-3p on Multiple Sclerosis pathology is suggested.
- Further research into the interplay of TNF and miR-142-3p in MS pathogenesis is warranted.
