Sex differences regulate immune responses in experimental autoimmune encephalomyelitis and multiple sclerosis

Ryan, Lucy; Mills, Kingston H. G.

doi:10.1002/eji.202149589

Cited by 21 publications

(17 citation statements)

References 96 publications

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“…Sex-related differences in innate and adaptive immune responses may account for a prevalent female susceptibility to develop EAE symptoms [30]. Myelin oligodendrocyte glycoprotein (MOG ) was used to induce chronic progressive EAE in CB57BL/6 female mice [31], and myelin proteolipid protein (PLP 139-151 ) was used to induce relapsing-remitting EAE in SJL female mice [32].…”

Section: Eae Inductionmentioning

confidence: 99%

Posttranscriptional Regulation of Gene Expression Participates in the Myelin Restoration in Mouse Models of Multiple Sclerosis: Antisense Modulation of HuR and HuD ELAV RNA Binding Protein

Borgonetti

Galeotti

2023

Mol Neurobiol

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Neuropathic pain is the most difficult-to-treat pain syndrome in multiple sclerosis. Evidence relates neuropathic pain to demyelination, which often originates from unresolved neuroinflammation or altered immune response. Posttranscriptional regulation of gene expression might play a fundamental role in the regulation of these processes. The ELAV RNA-binding proteins HuR and HuD are involved in the promotion of inflammatory phenomena and in neuronal development and maintenance, respectively. Thus, the aim of this study was to investigate the role of HuR and HuD in demyelination-associated neuropathic pain in the mouse experimental autoimmune encephalomyelitis (EAE) model. HuR resulted overexpressed in the spinal cord of MOG35-55–EAE and PLP139-151–EAE mice and was detected in CD11b + cells. Conversely, HuD was largely downregulated in the MOG–EAE spinal cord, along with GAP43 and neurofilament H, while in PLP-EAE mice, HuD and neuronal markers remained unaltered. Intranasal antisense oligonucleotide (ASO) delivery to knockdown HuR, increased myelin basic protein expression, and Luxol Fast Blue staining in both EAE models, an indication of increased myelin content. These effects temporally coincided with attenuation of pain hypersensitivity. Anti-HuR ASO increased the expression of HuD in GAP43-expressing cells and promoted a HuD-mediated neuroprotective activity in MOG–EAE mice, while in PLP–EAE mice, HuR silencing dampened pro-inflammatory responses mediated by spinal microglia activation. In conclusion, anti-HuR ASO showed myelin protection at analgesic doses with multitarget mechanisms, and it deserves further consideration as an innovative agent to counteract demyelination in neuropathic pain states. Graphical Abstract

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Section: Eae Inductionmentioning

confidence: 99%

Posttranscriptional Regulation of Gene Expression Participates in the Myelin Restoration in Mouse Models of Multiple Sclerosis: Antisense Modulation of HuR and HuD ELAV RNA Binding Protein

Borgonetti

Galeotti

2023

Mol Neurobiol

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“…Among the fumaric acid derivates, dimethyl fumarate (DMF) suppresses Th1/Th17 inflammatory responses and promotes a Th2-type response. It is also reported that DMF reduces IL-17 production by CD4 T cells [ 20 ]. Infusion and injectable DMTs are a group of monoclonal antibodies that are comprised of Natalizumab, which prevents lymphocyte adhesion and migration from the peripheral vascular bed to the CNS; Alemtuzumab, which selectively binds the CD52 protein, inducing the clearance of T and B cells and increasing the secretion of brain-derived neurotrophic factor (BDNF) [ 9 , 13 ]; Rituximab, which targets CD20; and Ocrelizumab, which induces an antibody-dependent cytolysis and complement-mediated lysis of B cells [ 9 ].…”

Section: Multiple Sclerosismentioning

confidence: 99%

Sex and Gender Differences in Neurodegenerative Diseases: Challenges for Therapeutic Opportunities

Bianco

Antonacci

Liguori

2023

IJMS

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The term “neurodegenerative diseases” (NDs) identifies a group of heterogeneous diseases characterized by progressive loss of selectively vulnerable populations of neurons, which progressively deteriorates over time, leading to neuronal dysfunction. Protein aggregation and neuronal loss have been considered the most characteristic hallmarks of NDs, but growing evidence confirms that significant dysregulation of innate immune pathways plays a crucial role as well. NDs vary from multiple sclerosis, in which the autoimmune inflammatory component is predominant, to more “classical” NDs, such as Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and spinal muscular atrophy. Of interest, many of the clinical differences reported in NDs seem to be closely linked to sex, which may be justified by the significant changes in immune mechanisms between affected females and males. In this review, we examined some of the most studied NDs by looking at their pathogenic and phenotypical features to highlight sex-related discrepancies, if any, with particular interest in the individuals’ responses to treatment. We believe that pointing out these differences in clinical practice may help achieve more successful precision and personalized care.

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“…Sex-related differences of innate and adaptive immune responses may account for a prevalent female susceptibility to develop EAE symptoms [25]. Myelin Oligodendrocyte Glycoprotein (MOG…”

Section: Eae Inductionmentioning

confidence: 99%

Myelin restoration by antisense modulation of HuR and HuD ELAV RNA binding protein expression in mouse models of multiple sclerosis

Borgonetti

Galeotti

2022

Preprint

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Neuropathic pain is the most difficult to treat pain syndrome in multiple sclerosis. Evidence relates neuropathic pain to demyelination that often originates from unresolved neuroinflammation or altered immune response. Post–transcriptional regulation of gene expression might play a fundamental role in the regulation of these processes and the aim of this study was to investigate ELAV RNA binding proteins in demyelination-associated neuropathic pain states. The ubiquitous HuR and the neuronal HuD are involved in inflammatory phenomena and neuronal development and maintenance, respectively. Thus, we investigated their role in the mouse experimental autoimmune encephalomyelitis (EAE) model. HuR resulted overexpressed in the spinal cord of MOG–EAE and PLP–EAE mice and was detected in CD11b+ cells. Intranasal delivery of an antisense oligonucleotide (ASO) to knockdown HuR increased myelin basic protein expression and Luxol Fast Blue staining, indication of increased myelin content, in both EAE models. These effects temporally coincided with attenuation of pain hypersensitivity. Conversely to HuR, HuD was largely downregulated in the MOG-EAE spinal cord, along with GAP43 and Neurofilament H, while in PLP-EAE mice HuD and neuronal markers remained unaltered. In MOG-EAE mice anti–HuR ASO increased the expression of HuD in GAP43 expressing cells and promoted a HuD–mediated neuroprotective activity. In PLP-EAE mice HuR silencing dampened pro–inflammatory response mediated by spinal microglia activation. In conclusion, anti–HuR ASO showed myelin protection at analgesic doses with multitarget mechanisms, and it deserves further consideration as an innovative agent to counteract demyelination in neuropathic pain states.

show abstract

Sex differences regulate immune responses in experimental autoimmune encephalomyelitis and multiple sclerosis

Cited by 21 publications

References 96 publications

Posttranscriptional Regulation of Gene Expression Participates in the Myelin Restoration in Mouse Models of Multiple Sclerosis: Antisense Modulation of HuR and HuD ELAV RNA Binding Protein

Posttranscriptional Regulation of Gene Expression Participates in the Myelin Restoration in Mouse Models of Multiple Sclerosis: Antisense Modulation of HuR and HuD ELAV RNA Binding Protein

Sex and Gender Differences in Neurodegenerative Diseases: Challenges for Therapeutic Opportunities

Myelin restoration by antisense modulation of HuR and HuD ELAV RNA binding protein expression in mouse models of multiple sclerosis

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