Interleukin-1β causes excitotoxic neurodegeneration and multiple sclerosis disease progression by activating the apoptotic protein p53

Molecular Neurodegeneration

Diego Centonze⁴  Jelena Drulovic¹  Roberto Furlan²  Gianvito Martino²  Luca Battistini⁴  Sagit Weiss⁴  Raffaele Mancino³  Annamaria Finardi²  Fabio Buttari⁴  Gabriella Ruocco⁴  Francesca Barbieri⁴  Elisabetta Volpe⁴  Giulia Macchiarulo⁴  Valeria Studer⁴  Caterina Motta⁵  Silvia Rossi⁵ 

[1] Clinic of Neurology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia;Neuroimmunology Unit, Institute of Experimental Neurology (INSpe), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy;Clinica Oculistica, Dipartimento di Biopatologia, Università Tor Vergata, Rome, Italy;Fondazione Santa Lucia/Centro Europeo per la Ricerca sul Cervello (CERC), Rome, Italy;IRCCS Istituto Neurologico Mediterraneo (INM) Neuromed, Pozzilli, Italy

关键词: Tumor necrosis factor-α;    Synaptic transmission;    MS;    Inflammation;    Glutamate;    Apoptosis;   

Others  :  1138622
DOI  :  10.1186/1750-1326-9-56

 received in 2014-09-24, accepted in 2014-12-03,  发布年份 2014

【 摘 要 】

Background

Understanding how inflammation causes neuronal damage is of paramount importance in multiple sclerosis (MS) and in other neurodegenerative diseases. Here we addressed the role of the apoptotic cascade in the synaptic abnormalities and neuronal loss caused by the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor (TNF-α) in brain tissues, and disease progression caused by inflammation in relapsing-remitting MS (RRMS) patients.

Results

The effect of IL-1β, but not of TNF-α, on glutamate-mediated excitatory postsynaptic currents was blocked by pifithrin-α (PFT), inhibitor of p53. The protein kinase C (PKC)/transient receptor potential vanilloid 1 (TRPV1) pathway was involved in IL-1β-p53 interaction at glutamatergic synapses, as pharmacological modulation of this inflammation-relevant molecular pathway affected PFT effects on the synaptic action of IL-1β. IL-1β-induced neuronal swelling was also blocked by PFT, and IL-1β increased the expression of p21, a canonical downstream target of activated p53.

Consistent with these in vitro results, the Pro/Pro genotype of p53, associated with low efficiency of transcription of p53-regulated genes, abrogated the association between IL-1β cerebrospinal fluid (CSF) levels and disability progression in RRMS patients. The interaction between p53 and CSF IL-1β was also evaluated at the optical coherence tomography (OCT), showing that IL-1β-driven neurodegenerative damage, causing alterations of macular volume and of retinal nerve fibre layer thickness, was modulated by the p53 genotype.

Conclusions

Inflammatory synaptopathy and neurodegeneration caused by IL-1β in RRMS patients involve the apoptotic cascade. Targeting IL-1β-p53 interaction might result in significant neuroprotection in MS.

【 授权许可】

   
2014 Rossi et al.; licensee BioMed Central.

【 图 表 】

Figure 2.

Figure 3.

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