Emerging role of extracellular vesicles in multiple sclerosis: From cellular surrogates to pathogenic mediators and beyond

Palacio, Paola Loreto; Pleet, Michelle L.; Reátegui, Eduardo; Magaña, Setty M.

doi:10.1016/j.jneuroim.2023.578064

Cited by 7 publications

(6 citation statements)

References 318 publications

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“…The intricacies of demyelinating disorders, particularly MS, in comprehending their pathogenesis and devising efficient therapeutic measures are substantial (Palacio et al, 2023). In this context, our comparative study centers on recent inquiries observing diverse intervention modalities in both CPZ‐induced demyelination and EAE models.…”

Section: Discussionmentioning

confidence: 99%

AMP‐activated protein kinase as a mediator of mitochondrial dysfunction of multiple sclerosis in animal models: A systematic review

Askari,

Rabiei,

Lohrasbi

et al. 2024

Journal Cellular Physiology

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Multiple sclerosis (MS) is a chronic central nervous system (CNS) disorder characterized by demyelination, neuronal damage, and oligodendrocyte depletion. Reliable biomarkers are essential for early diagnosis and disease management. Emerging research highlights the role of mitochondrial dysfunction and oxidative stress in CNS disorders, including MS, in which mitochondria are central to the degenerative process. Adenosine monophosphate‐activated protein kinase (AMPK) regulates the mitochondrial energy balance and initiates responses in neurodegenerative conditions. This systematic review, following Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines, aimed to comprehensively assess the literature on AMPK pathways, mitochondrial dysfunction, and in vivo studies using MS animal models. The search strategy involved the use of AMPK syntaxes, MS syntaxes, and animal model syntaxes. The PubMed, Scopus, Web of Science, and Google Scholar databases were systematically searched on August 26, 2023 without publication year restrictions. The review identified and analyzed relevant papers to provide a comprehensive overview of the current state of related research. Eight studies utilizing various interventions and methodological approaches were included. Risk of bias assessment revealed some areas of low risk but lacked explicit reporting in others. These studies collectively revealed a complex relationship between AMPK, mitochondrial dysfunction, and MS pathogenesis, with both cuprizone and experimental autoimmune encephalomyelitis models demonstrating associations between AMPK and mitochondrial disorders, including oxidative stress and impaired expression of mitochondrial genes. These studies illuminate the multifaceted role of AMPK in MS animal models, involving energy metabolism, inflammatory processes, oxidative stress, and gene regulation leading to mitochondrial dysfunction. However, unanswered questions about its mechanisms and clinical applications underscore the need for further research to fully harness its potential in addressing MS‐related mitochondrial dysfunction.

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Section: Discussionmentioning

confidence: 99%

AMP‐activated protein kinase as a mediator of mitochondrial dysfunction of multiple sclerosis in animal models: A systematic review

Askari,

Rabiei,

Lohrasbi

et al. 2024

Journal Cellular Physiology

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“…Cytokines and chemokines have long been known to be immune response mediators. Recent research has focused on EVs as novel particles mediating immune responses [ 31 , 32 , 33 ]. Our results indicate that the titers of anti-EBNA1 in the blood EVs of patients with MS could be involved in MS relapses and serve as a biomarker of disease activity.…”

Section: Discussionmentioning

confidence: 99%

Antibody Content against Epstein–Barr Virus in Blood Extracellular Vesicles Correlates with Disease Activity and Brain Volume in Patients with Relapsing–Remitting Multiple Sclerosis

Fernández-Fournier,

López-Molina,

Torres Iglesias

et al. 2023

IJMS

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We aimed to analyze whether EVs carry antibodies against EBV antigens and the possibility that they could serve as diagnostic and disease activity blood biomarkers in RRMS. This was a prospective and observational study including patients with RRMS with active and inactive disease and healthy controls. Blood EVs were isolated by precipitation. Titers of antibodies against nuclear (anti-EBNA1) and capsid (anti-VCA) EBV antigens in EVs and in plasma, as well as content of myelin antibodies in EVs were determined by ELISA. An exploratory analysis of correlations with clinical and radiological data was performed. Patients with RRMS had higher titers of anti-VCA inside EVs and free in plasma than healthy controls. Patients with active disease showed higher levels of anti-EBNA1 in EVs, but not in plasma, than patients with inactive disease. EV anti-VCA levels correlated with disease duration and with decreased brain volume structures—total brain, white matter, gray matter, cerebellum, hippocampus, —but not with T2/FLAIR lesion volume or EDSS, SDMT, or 9HPT. In addition, EV anti-VCA correlated with EV anti-MBP. The anti-VCA and anti-EBNA1 content in EVs could represent diagnostic and disease activity blood biomarkers, respectively, in RRMS.

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“…Depending on the origin cells, these messages correspond to several molecules, including lipids, proteins, and nucleic acids, as well as having different biological significance, resulting in functional modifications of target cells, for example, in both pro-inflammatory and anti-inflammatory senses. Consistently, growing evidence indicates that EVs are important players in autoimmune disorders, including multiple sclerosis (MS), a chronic autoimmune disease [1][2][3]. In spite of their emerging importance in the physiology of cells and organs, these structures are currently underexplored.…”

Section: Introductionmentioning

confidence: 99%

Ultrastructural Characterization of PBMCs and Extracellular Vesicles in Multiple Sclerosis: A Pilot Study

De Masi,

Orlando,

Carata

et al. 2024

IJMS

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Growing evidence identifies extracellular vesicles (EVs) as important cell-to-cell signal transducers in autoimmune disorders, including multiple sclerosis (MS). If the etiology of MS still remains unknown, its molecular physiology has been well studied, indicating peripheral blood mononuclear cells (PBMCs) as the main pathologically relevant contributors to the disease and to neuroinflammation. Recently, several studies have suggested the involvement of EVs as key mediators of neuroimmune crosstalk in central nervous system (CNS) autoimmunity. To assess the role of EVs in MS, we applied electron microscopy (EM) techniques and Western blot analysis to study the morphology and content of plasma-derived EVs as well as the ultrastructure of PBMCs, considering four MS patients and four healthy controls. Through its exploratory nature, our study was able to detect significant differences between groups. Pseudopods and large vesicles were more numerous at the plasmalemma interface of cases, as were endoplasmic vesicles, resulting in an activated aspect of the PBMCs. Moreover, PBMCs from MS patients also showed an increased number of multivesicular bodies within the cytoplasm and amorphous material around the vesicles. In addition, we observed a high number of plasma-membrane-covered extensions, with multiple associated large vesicles and numerous autophagosomal vacuoles containing undigested cytoplasmic material. Finally, the study of EV cargo evidenced a number of dysregulated molecules in MS patients, including GANAB, IFI35, Cortactin, Septin 2, Cofilin 1, and ARHGDIA, that serve as inflammatory signals in a context of altered vesicular dynamics. We concluded that EM coupled with Western blot analysis applied to PBMCs and vesiculation can enhance our knowledge in the physiopathology of MS.

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Emerging role of extracellular vesicles in multiple sclerosis: From cellular surrogates to pathogenic mediators and beyond

Cited by 7 publications

References 318 publications

AMP‐activated protein kinase as a mediator of mitochondrial dysfunction of multiple sclerosis in animal models: A systematic review

AMP‐activated protein kinase as a mediator of mitochondrial dysfunction of multiple sclerosis in animal models: A systematic review

Antibody Content against Epstein–Barr Virus in Blood Extracellular Vesicles Correlates with Disease Activity and Brain Volume in Patients with Relapsing–Remitting Multiple Sclerosis

Ultrastructural Characterization of PBMCs and Extracellular Vesicles in Multiple Sclerosis: A Pilot Study

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