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Role of Extracellular Vesicles in Immunology
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Role of Extracellular Vesicles in Immunology

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (20 October 2024) | Viewed by 15892

Special Issue Editors

Dr. Paolo Colombo

E-Mail Website
Guest Editor
Institute for Biomedical Research and Innovation, National Research Council, Via Ugo La Malfa 153, 90146 Palermo, Italy
Interests: immune system; allergic diseases; extracellular vesicles; immunotherapy; nanoparticles
Special Issues, Collections and Topics in MDPI journals
Dr. Valeria Longo

E-Mail Website
Guest Editor
Institute for Biomedical Research and Innovation, National Research Council of Italy (IRIB-CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy
Interests: immune response; innate immunity; cell to cell communication; extracellular vesicles cargo; epigenetic modification; miRNA; environmental pollutants; immunotoxicity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cells can communicate in different ways by means of soluble factors or cell-to-cell contact; however, an increasing body of evidence has recently demonstrated that cells can communicate through the release of extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies. EVs are particles composed of an outer lipid bilayer of variable size that, during the immune response, are selectively loaded with immune regulatory proteins, such as cytokines, which makes them important messengers delivering targeted biological signals. The vesicular signalling now emerges as a critical component of innate immunity that orchestrates actions of multiple immune system cells in infectious and inflammatory diseases. It is interesting to note that EVs are highly heterogeneous concerning their composition, location, and function as indicated by their parental cells. The cargo transfer regulates various cellular activities ranging from gene expression to metabolism. Of note, the number of EVs produced and the cargos loaded into these extracellular vesicles depends on the state (physiological or pathological) and microenvironment of the donor cells also opening the way to the relevance of EVs and their cargo content for human toxicology studies. Indeed, EVs isolated from patient body fluids have been studied in research concerning disease biomarkers and early diagnosis possibilities in inflammatory diseases as atherosclerosis, Alzheimer’s disease and rheumatoid arthritis.

In this Special Issue, we welcome manuscripts addressing original research and review papers as well as short communications highlighting the characteristics of EVs. Topics of interest include, but are not limited to, the following:

  • Immunological response (innate and adaptive immunity, including inflammation, antigen presentation, and the development and activation of B cells and T cells);
  • Characterization of EVs’ cargo content (microRNAs, lipids, mRNAs, etc);
  • Next-generation drug delivery platforms;
  • Relevance of EVs in human toxicology studies.

Dr. Paolo Colombo
Dr. Valeria Longo
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Related Special Issue

Published Papers (8 papers)

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Research

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23 pages, 6877 KiB  
Article
Hypoxic Human Microglia Promote Angiogenesis Through Extracellular Vesicle Release
by Alessandra Maria Testa, Livia Vignozzi, Diana Corallo, Sanja Aveic, Antonella Viola, Manuela Allegra and Roberta Angioni
Int. J. Mol. Sci. 2024, 25(23), 12508; https://doi.org/10.3390/ijms252312508 - 21 Nov 2024
Viewed by 313
Abstract
Microglia, the brain-resident immune cells, orchestrate neuroinflammatory responses and are crucial in the progression of neurological diseases, including ischemic stroke (IS), which accounts for approximately 85% of all strokes worldwide. Initially deemed detrimental, microglial activation has been shown to perform protective functions in [...] Read more.
Microglia, the brain-resident immune cells, orchestrate neuroinflammatory responses and are crucial in the progression of neurological diseases, including ischemic stroke (IS), which accounts for approximately 85% of all strokes worldwide. Initially deemed detrimental, microglial activation has been shown to perform protective functions in the ischemic brain. Besides their effects on neurons, microglia play a role in promoting post-ischemic angiogenesis, a pivotal step for restoring oxygen and nutrient supply. However, the molecular mechanisms underlying microglia–endothelial cell interactions remain largely unresolved, particularly in humans. Using both in vitro and in vivo models, we investigated the angiogenic signature and properties of extracellular vesicles (EVs) released by human microglia upon hypoxia–reperfusion stimulation. EVs were isolated and characterized in terms of their size, concentration, and protein content. Their angiogenic potential was evaluated using endothelial cell assays and a zebrafish xenograft model. The in vivo effects were further assessed in a mouse model of ischemic stroke. Our findings identified key proteins orchestrating the pro-angiogenic functions of human microglial EVs under hypoxic conditions. In vitro assays demonstrated that hypoxic EVs (hypEVs) promoted endothelial cell migration and tube formation. In vivo, hypEVs induced vessel sprouting in zebrafish and increased microvessel density in the perilesional area of mice following ischemic stroke. Full article
(This article belongs to the Special Issue Role of Extracellular Vesicles in Immunology)
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24 pages, 38571 KiB  
Article
Signature Proteins in Small Extracellular Vesicles of Granulocytes and CD4+ T-Cell Subpopulations Identified by Comparative Proteomic Analysis
by Sara Vázquez-Mera, Pablo Miguéns-Suárez, Laura Martelo-Vidal, Sara Rivas-López, Lena Uller, Susana B. Bravo, Vicente Domínguez-Arca, Xavier Muñoz, Francisco J. González-Barcala, Juan J. Nieto Fontarigo and Francisco J. Salgado
Int. J. Mol. Sci. 2024, 25(19), 10848; https://doi.org/10.3390/ijms251910848 - 9 Oct 2024
Viewed by 1144
Abstract
Several studies have described the proteomic profile of different immune cell types, but only a few have also analysed the content of their delivered small extracellular vesicles (sEVs). The aim of the present study was to compare the protein signature of sEVs delivered [...] Read more.
Several studies have described the proteomic profile of different immune cell types, but only a few have also analysed the content of their delivered small extracellular vesicles (sEVs). The aim of the present study was to compare the protein signature of sEVs delivered from granulocytes (i.e., neutrophils and eosinophils) and CD4+ T cells (i.e., TH1, TH2, and TH17) to identify potential biomarkers of the inflammatory profile in chronic inflammatory diseases. Qualitative (DDA) and quantitative (DIA-SWATH) analyses of in vitro-produced sEVs revealed proteome variations depending on the cell source. The main differences were found between granulocyte- and TH cell-derived sEVs, with a higher abundance of antimicrobial proteins (e.g., LCN2, LTF, MPO) in granulocyte-derived sEVs and an enrichment of ribosomal proteins (RPL and RPS proteins) in TH-derived sEVs. Additionally, we found differentially abundant proteins between neutrophil and eosinophil sEVs (e.g., ILF2, LTF, LCN2) and between sEVs from different TH subsets (e.g., ISG15, ITGA4, ITGB2, or NAMPT). A “proof-of-concept” assay was also performed, with TH2 biomarkers ITGA4 and ITGB2 displaying a differential abundance in sEVs from T2high and T2low asthma patients. Thus, our findings highlight the potential use of these sEVs as a source of biomarkers for diseases where the different immune cell subsets studied participate, particularly chronic inflammatory pathologies such as asthma or chronic obstructive pulmonary disease (COPD). Full article
(This article belongs to the Special Issue Role of Extracellular Vesicles in Immunology)
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16 pages, 2826 KiB  
Article
Generation of Myeloid-Derived Suppressor Cells Mediated by MicroRNA-125a-5p in Melanoma
by Samantha Lasser, Feyza Gul Ozbay Kurt, Lennart Fritz, Nina Gutzeit, Carolina De La Torre, Peter Altevogt, Jochen Utikal and Viktor Umansky
Int. J. Mol. Sci. 2024, 25(12), 6693; https://doi.org/10.3390/ijms25126693 - 18 Jun 2024
Viewed by 960
Abstract
The ability of tumor-derived extracellular vesicles (EVs) to modulate the function of myeloid cells is widely recognized. Hence, a comprehensive understanding of the distinct components associated with EVs and the signals that they deliver to myeloid cells could provide potential approaches to impede [...] Read more.
The ability of tumor-derived extracellular vesicles (EVs) to modulate the function of myeloid cells is widely recognized. Hence, a comprehensive understanding of the distinct components associated with EVs and the signals that they deliver to myeloid cells could provide potential approaches to impede the immunosuppression by myeloid-derived suppressor cells (MDSCs). We investigated melanoma EV-associated microRNAs (miRs) using the RET transgenic melanoma mouse model and simulated their transfer to normal myeloid cells by transfecting immature mouse myeloid cells and human monocytes. We observed elevated levels of miR-125a-5p, -125b-5p, and let-7e-5p in mouse melanoma-infiltrating MDSCs. In addition, miR-125a-5p levels in the tumor microenvironment correlated with mouse melanoma progression. The delivery of miR-125a-5p, alone or in combination with let-7e-5p and miR-99b-5p from the same genomic cluster, to normal myeloid cells resulted in their conversion to MDSC-like cells. Our findings indicate that miR-125a-5p could modulate myeloid cell activation in the melanoma microenvironment via a NF-κB-dependent mechanism. Full article
(This article belongs to the Special Issue Role of Extracellular Vesicles in Immunology)
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30 pages, 4965 KiB  
Article
Unraveling the Impact of Extracellular Vesicle-Depleted Serum on Endothelial Cell Characteristics over Time
by Luiz Fernando Cardoso Garcia, Pryscilla Fanini Wowk and Letusa Albrecht
Int. J. Mol. Sci. 2024, 25(9), 4761; https://doi.org/10.3390/ijms25094761 - 27 Apr 2024
Viewed by 1614
Abstract
Extracellular vesicles (EVs) are produced by all kinds of cells, including endothelial cells. It has been observed that EVs present in fetal bovine serum (FBS), broadly used in cell culture, can be a confounding factor and lead to misinterpretation of results. To investigate [...] Read more.
Extracellular vesicles (EVs) are produced by all kinds of cells, including endothelial cells. It has been observed that EVs present in fetal bovine serum (FBS), broadly used in cell culture, can be a confounding factor and lead to misinterpretation of results. To investigate this phenomenon, human brain microvascular endothelial cells (HBMECs) were cultured for 2 or 24 h in the presence of EV-depleted FBS (EVdS). Cell death, gene and protein expression, and the presence of EVs isolated from these cells were evaluated. The uptake of EVs, intercellular adhesion molecule 1 (ICAM-1) expression, and monocyte adhesion to endothelial cells exposed to EVs were also evaluated. Our results revealed higher apoptosis rates in cells cultured with EVdS for 2 and 24 h. There was an increase in interleukin 8 (IL8) expression after 2 h and a decrease in interleukin 6 (IL6) and IL8 expression after 24 h of culture. Among the proteins identified in EVs isolated from cells cultured for 2 h (EV2h), several were related to ribosomes and carbon metabolism. EVs from cells cultured for 24 h (EV24h) presented a protein profile associated with cell adhesion and platelet activation. Additionally, HBMECs exhibited increased uptake of EV2h. Treatment of endothelial cells with EV2h resulted in greater ICAM-1 expression and greater adherence to monocytes than did treatment with EV24h. According to our data, HBMEC cultivated with EVdS produce EVs with different physical characteristics and protein levels that vary over time. Full article
(This article belongs to the Special Issue Role of Extracellular Vesicles in Immunology)
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Review

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26 pages, 1229 KiB  
Review
Oral Pathobiont-Derived Outer Membrane Vesicles in the Oral–Gut Axis
by Eduardo A. Catalan, Emilio Seguel-Fuentes, Brandon Fuentes, Felipe Aranguiz-Varela, Daniela P. Castillo-Godoy, Elizabeth Rivera-Asin, Elisa Bocaz, Juan A. Fuentes, Denisse Bravo, Katina Schinnerling and Felipe Melo-Gonzalez
Int. J. Mol. Sci. 2024, 25(20), 11141; https://doi.org/10.3390/ijms252011141 - 17 Oct 2024
Viewed by 930
Abstract
Oral pathobionts are essential in instigating local inflammation within the oral cavity and contribute to the pathogenesis of diseases in the gastrointestinal tract and other distant organs. Among the Gram-negative pathobionts, Porphyromonas gingivalis and Fusobacterium nucleatum emerge as critical drivers of periodontitis, exerting [...] Read more.
Oral pathobionts are essential in instigating local inflammation within the oral cavity and contribute to the pathogenesis of diseases in the gastrointestinal tract and other distant organs. Among the Gram-negative pathobionts, Porphyromonas gingivalis and Fusobacterium nucleatum emerge as critical drivers of periodontitis, exerting their influence not only locally but also as inducers of gut dysbiosis, intestinal disturbances, and systemic ailments. This dual impact is facilitated by their ectopic colonization of the intestinal mucosa and the subsequent mediation of distal systemic effects by releasing outer membrane vesicles (OMVs) into circulation. This review elucidates the principal components of oral pathobiont-derived OMVs implicated in disease pathogenesis within the oral–gut axis, detailing virulence factors that OMVs carry and their interactions with host epithelial and immune cells, both in vitro and in vivo. Additionally, we shed light on the less acknowledged interplay between oral pathobionts and the gut commensal Akkermansia muciniphila, which can directly impede oral pathobionts’ growth and modulate bacterial gene expression. Notably, OMVs derived from A. muciniphila emerge as promoters of anti-inflammatory effects within the gastrointestinal and distant tissues. Consequently, we explore the potential of A. muciniphila-derived OMVs to interact with oral pathobionts and prevent disease in the oral–gut axis. Full article
(This article belongs to the Special Issue Role of Extracellular Vesicles in Immunology)
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32 pages, 2988 KiB  
Review
The Role of Bacterial Extracellular Vesicles in the Immune Response to Pathogens, and Therapeutic Opportunities
by Eliud S. Peregrino, Jessica Castañeda-Casimiro, Luis Vázquez-Flores, Sergio Estrada-Parra, Carlos Wong-Baeza, Jeanet Serafín-López and Isabel Wong-Baeza
Int. J. Mol. Sci. 2024, 25(11), 6210; https://doi.org/10.3390/ijms25116210 - 5 Jun 2024
Cited by 2 | Viewed by 2888
Abstract
Pathogenic bacteria have several mechanisms to evade the host’s immune response and achieve an efficient infection. Bacterial extracellular vesicles (EVs) are a relevant cellular communication mechanism, since they can interact with other bacterial cells and with host cells. In this review, we focus [...] Read more.
Pathogenic bacteria have several mechanisms to evade the host’s immune response and achieve an efficient infection. Bacterial extracellular vesicles (EVs) are a relevant cellular communication mechanism, since they can interact with other bacterial cells and with host cells. In this review, we focus on the EVs produced by some World Health Organization (WHO) priority Gram-negative and Gram-positive pathogenic bacteria; by spore-producing bacteria; by Mycobacterium tuberculosis (a bacteria with a complex cell wall); and by Treponema pallidum (a bacteria without lipopolysaccharide). We describe the classification and the general properties of bacterial EVs, their role during bacterial infections and their effects on the host immune response. Bacterial EVs contain pathogen-associated molecular patterns that activate innate immune receptors, which leads to cytokine production and inflammation, but they also contain antigens that induce the activation of B and T cell responses. Understanding the many effects of bacterial EVs on the host’s immune response can yield new insights on the pathogenesis of clinically important infections, but it can also lead to the development of EV-based diagnostic and therapeutic strategies. In addition, since EVs are efficient activators of both the innate and the adaptive immune responses, they constitute a promising platform for vaccine development. Full article
(This article belongs to the Special Issue Role of Extracellular Vesicles in Immunology)
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20 pages, 753 KiB  
Review
Extracellular Vesicles and Immunity: At the Crossroads of Cell Communication
by Noemi Aloi, Gaspare Drago, Silvia Ruggieri, Fabio Cibella, Paolo Colombo and Valeria Longo
Int. J. Mol. Sci. 2024, 25(2), 1205; https://doi.org/10.3390/ijms25021205 - 18 Jan 2024
Cited by 12 | Viewed by 3845
Abstract
Extracellular vesicles (EVs), comprising exosomes and microvesicles, are small membranous structures secreted by nearly all cell types. They have emerged as crucial mediators in intercellular communication, playing pivotal roles in diverse physiological and pathological processes, notably within the realm of immunity. These roles [...] Read more.
Extracellular vesicles (EVs), comprising exosomes and microvesicles, are small membranous structures secreted by nearly all cell types. They have emerged as crucial mediators in intercellular communication, playing pivotal roles in diverse physiological and pathological processes, notably within the realm of immunity. These roles go beyond mere cellular interactions, as extracellular vesicles stand as versatile and dynamic components of immune regulation, impacting both innate and adaptive immunity. Their multifaceted involvement includes immune cell activation, antigen presentation, and immunomodulation, emphasising their significance in maintaining immune homeostasis and contributing to the pathogenesis of immune-related disorders. Extracellular vesicles participate in immunomodulation by delivering a wide array of bioactive molecules, including proteins, lipids, and nucleic acids, thereby influencing gene expression in target cells. This manuscript presents a comprehensive review that encompasses in vitro and in vivo studies aimed at elucidating the mechanisms through which EVs modulate human immunity. Understanding the intricate interplay between extracellular vesicles and immunity is imperative for unveiling novel therapeutic targets and diagnostic tools applicable to various immunological disorders, including autoimmune diseases, infectious diseases, and cancer. Furthermore, recognising the potential of EVs as versatile drug delivery vehicles holds significant promise for the future of immunotherapies. Full article
(This article belongs to the Special Issue Role of Extracellular Vesicles in Immunology)
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19 pages, 911 KiB  
Review
Lipid Metabolism Modulation during SARS-CoV-2 Infection: A Spotlight on Extracellular Vesicles and Therapeutic Prospects
by Heloisa D’Avila, Claudia Natércia Rocha Lima, Pollianne Garbero Rampinelli, Laiza Camila Oliveira Mateus, Renata Vieira de Sousa Silva, José Raimundo Correa and Patrícia Elaine de Almeida
Int. J. Mol. Sci. 2024, 25(1), 640; https://doi.org/10.3390/ijms25010640 - 4 Jan 2024
Cited by 7 | Viewed by 3132
Abstract
Extracellular vesicles (EVs) have a significant impact on the pathophysiological processes associated with various diseases such as tumors, inflammation, and infection. They exhibit molecular, biochemical, and entry control characteristics similar to viral infections. Viruses, on the other hand, depend on host metabolic machineries [...] Read more.
Extracellular vesicles (EVs) have a significant impact on the pathophysiological processes associated with various diseases such as tumors, inflammation, and infection. They exhibit molecular, biochemical, and entry control characteristics similar to viral infections. Viruses, on the other hand, depend on host metabolic machineries to fulfill their biosynthetic requirements. Due to potential advantages such as biocompatibility, biodegradation, and efficient immune activation, EVs have emerged as potential therapeutic targets against the SARS-CoV-2 infection. Studies on COVID-19 patients have shown that they frequently have dysregulated lipid profiles, which are associated with an increased risk of severe repercussions. Lipid droplets (LDs) serve as organelles with significant roles in lipid metabolism and energy homeostasis as well as having a wide range of functions in infections. The down-modulation of lipids, such as sphingolipid ceramide and eicosanoids, or of the transcriptional factors involved in lipogenesis seem to inhibit the viral multiplication, suggesting their involvement in the virus replication and pathogenesis as well as highlighting their potential as targets for drug development. Hence, this review focuses on the role of modulation of lipid metabolism and EVs in the mechanism of immune system evasion during SARS-CoV-2 infection and explores the therapeutic potential of EVs as well as application for delivering therapeutic substances to mitigate viral infections. Full article
(This article belongs to the Special Issue Role of Extracellular Vesicles in Immunology)
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