Targeting the RNA-Binding Protein HuR Alleviates Neuroinflammation in Experimental Autoimmune Encephalomyelitis: Potenti
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ORIGINAL ARTICLE
Targeting the RNA-Binding Protein HuR Alleviates Neuroinflammation in Experimental Autoimmune Encephalomyelitis: Potential Therapy for Multiple Sclerosis Vittoria Borgonetti 1 & Maria Domenica Sanna 1 & Laura Lucarini 1 & Nicoletta Galeotti 1 Accepted: 22 October 2020 # The Author(s) 2020
Abstract Multiple sclerosis (MS) is a chronic autoimmune inflammatory and neurodegenerative disease of the central nervous system characterized by demyelination, axonal loss, and motor dysfunction. Activated microglia are associated with the destruction of myelin in the CNS. Activated microglia produce cytokines and proinflammatory factors, favoring neuroinflammation, myelin damage, and neuronal loss, and it is thought to be involved in the disease pathogenesis. The present study investigated the role of post-transcriptional regulation of gene expression on the neuroinflammation related to experimental autoimmune encephalomyelitis (EAE) in mice, by focusing on HuR, an RNA-binding protein involved in inflammatory and immune phenomena. Spinal cord sections of EAE mice showed an increased HuR immunostaining that was abundantly detected in the cytoplasm of activated microglia, a pattern associated with its increased activity. Intrathecal administration of an anti-HuR antisense oligonucleotide (ASO) decreased the proinflammatory activated microglia, inflammatory infiltrates, and the expression of the proinflammatory cytokines IL-1β, TNF-α, and IL-17, and inhibited the activation of the NF-κB pathway. The beneficial effect of anti-HuR ASO in EAE mice corresponded also to a decreased permeability of the blood–brain barrier. EAE mice showed a reduced spinal CD206 immunostaining that was restored by anti-HuR ASO, indicating that HuR silencing promotes a shift to the antiinflammatory and regenerative microglia phenotype. Mice that received anti-HuR ASO exhibited improved EAE-related motor dysfunction, pain hypersensitivity, and body weight loss. Targeting HuR might represent an innovative and promising perspective to control neurological disturbances in MS patients. Keywords multiple sclerosis . HuR . relapsing–remitting experimental autoimmune encephalomyelitis . microglia . cytokines . blood–brain barrier
Introduction Multiple sclerosis (MS) is a neurodegenerative disease affecting an estimated 2.9 people per 1000 [1]. MS is considered to be a chronic inflammatory disease driven by T-cell activity [2], followed by a degenerative process resulting in loss of the CNS myelin sheath and damage to the blood–brain barrier Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s13311-02000958-8. * Nicoletta Galeotti [email protected] 1
Section of Pharmacology, Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Viale G. Pieraccini 6, 50139 Florence, Italy
(BBB). Current MS treatment strategies are based on antiinflammatory drugs or immunosuppressant agents to moderate effects of immune attacks in the
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