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EDITORIAL article

Front. Cell Dev. Biol., 28 August 2023
Sec. Molecular and Cellular Pathology
This article is part of the Research Topic Extracellular Vesicles as Potent Modulators of Immunity View all 5 articles

Editorial: Extracellular vesicles as potent modulators of immunity

  • 1Department of Immunology, Jagiellonian University Medical College, Krakow, Poland
  • 2Department of Cell Biology, Faculty of Biological Sciences, Complutense University of Madrid, Madrid, Spain
  • 3Immunology Unit from Hospital Universitario de La Princesa, Universidad Autónoma de Madrid and Instituto de Investigación Sanitaria La Princesa (IIS-IP), Madrid, Spain
  • 4Intercellular Communication in the Inflammatory Response, Vascular Pathophysiology Area, National Center for Cardiovascular Research (CNIC), Madrid, Spain
  • 5Section of Rheumatology, Allergy and Clinical Immunology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, United States

For over 20 years, the research on membranous nanoparticles produced and released extracellularly by virtually all cells of living organisms has been developing more and more intensively, resembling a snowball rolling down the slope. In 2011, the term extracellular vesicles (EVs) was introduced into common use, defining all cell-secreted particles with a bilayer lipid membrane, and efforts were made to standardize the nomenclature of EV’s subpopulations, as well as techniques for their isolation from various biological materials, which is supervised by the International Society for Extracellular Vesicles (ISEV) (Buzas, 2023).

Although the important role of EVs in biological processes is beyond doubt, numerous studies are being undertaken to fully understand their specific functions in particular physiological and pathological conditions, such as tumorigenesis and inflammatory diseases (Buzas, 2023). The goal of this Research Topic was to present and discuss the recent findings and future perspectives on EV’s biology and functions in modulation of various immune processes with the special focus on tumor-related immunity as well as on allergic and autoimmune responses.

Among other cargoes, EVs convey a variety of bioactive lipids that are encapsulated and/or surface-expressed and play an important but understudied role in EV-induced immunomodulatory effects. Along these lines, Paolino et al. experimentally compared the lipidomes of microvesicle and exosome EV fractions between psoriatic patients and healthy controls, showing the significantly higher concentrations of phospholipids (phosphatidylcholine, phosphatidylethanolamine and phosphatidylglycerol) in psoriasis-related exosomes. Moreover, the Authors investigated the possible changes in the lipid profile of EVs isolated from plasma of psoriatic patients caused by the treatment with monoclonal antibodies against IL-17A, TNFα or IL-12/IL-23p40, and found that therapeutic administration of ustekinumab (a monoclonal antibody against p40, a common subunit of IL-12 and IL-23) restores phosphatidylcholine and phosphatidylethanolamine levels in plasma exosomes to levels detectable in healthy subjects. Thus, it was suggested that phospholipid determination in circulating EVs could serve as a diagnostic determinant and a promising biomarker of drug response in psoriatic patients.

Since EVs can cross anatomical barriers, they are also considered interesting candidates for monitoring processes in healthy and injured immune-privileged organs, such as the brain. Moreover, EVs have been widely studied in the context of intracellular communication between tumors and their microenvironment, promoting an immunosuppressive phenotype. Accordingly, Low et al. summarized the current research data on the impact of EVs on intercellular communication in neoplastic diseases of the central nervous system (CNS) with a special focus on glioblastoma. In most reviewed studies, EVs secreted by glioblastoma cells have been found to promote tumor cell growth and division in an immunosuppressive microenvironment driven by M2 macrophages that provide proangiogenic and promitotic factors. In addition, the Authors highlight the role of direct dysregulation of the activity of particular populations of myeloid cells, T and B lymphocytes, and natural killer cells in the immune suppression induced by tumor-derived EVs. It is worth noting that the blood-CSN barrier itself separates immune cells from the immune-privileged organ, which provides physiological immunotolerance, but also significantly impairs the cellular immune response against tumor cells and infectious viruses.

On the other hand, EVs are extensively investigated to uncover their therapeutic potential. EV-based therapies offer important advantages, consisting on cell-free approaches, that are biocompatible, showing low cytotoxicity and immunogenicity. However, these treatments exhibit disadvantages limiting their use in clinics, such as low stability and delivery efficiency or the uncontrolled specificity of their cargo. In this issue, Liu et al. focused their review article on the role of engineered EVs in the treatment of various inflammatory diseases. In addition to discussing and comparing the cargos of natural and modified EVs, the Authors recapitulate the technics of EV’s modification, applicable routes of their therapeutic delivery and finally the possible targets and outcomes of such therapy in pathologies of the respiratory, digestive, cardiovascular, genitourinary, reproductive, osteoarticular, nervous, immunological and hematological systems.

When considering the therapeutic use of EVs, their bioavailability, which could be limited by the mononuclear phagocyte system (MPS), cannot be overlooked. Namely, studies on the biodistribution of therapeutically administered EVs have shown that they can reach various distant organs, but are detected in the greatest amounts in MPS-enriched tissues of the liver, spleen, kidneys and lungs. These observations suggest that MPS cells rapidly clear exogenous EVs from the circulation, limiting the bioavailability of EV-based therapeutics. Therefore, researchers are now proposing novel strategies to avoid EV removal by MPS cells, as summarized by Cieślik et al. However, Cieślik et al. also point to mononuclear phagocytes as desired EV’s recipients that then can multiply and/or remake EV-delivered signaling to enhance its specificity and enable effective targeting of ultimate acceptor cells. Moreover, the Authors suggest that EVs may produce therapeutic effects by modulating malfunctioning MPS cells in various inflammatory diseases, for example, by restoring dysregulated activity and unbalanced polarization of macrophages.

Such a rapidly growing research field opens countless possibilities for the practical application of new knowledge about EVs, which, however, requires overcoming many limitations and challenges (van Niel et al., 2022), especially when considering EVs as tools for drug delivery (Elsharkasy et al., 2020). This Research Topic provided a platform for organizing the recent findings and future perspectives on EV’s biology and functions in various immune-related processes. We hope that the published results and conclusions will become an impulse for new research discoveries to overcome some of the current drawbacks for EV-based therapies in a way that will determine the future directions of clinical practice.

Author contributions

KB: Conceptualization, Writing–original draft, Writing–review and editing. LF-M: Writing–original draft, Writing–review and editing. PA: Writing–original draft. KN: Writing–original draft, Writing–review and editing.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

Buzas, E. I. (2023). The roles of extracellular vesicles in the immune system. Nat. Rev. Immunol. 23 (4), 236–250. doi:10.1038/s41577-022-00763-8

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van Niel, G., Carter, D. R. F., Clayton, A., Lambert, D. W., Raposo, G., and Vader, P. (2022). Challenges and directions in studying cell-cell communication by extracellular vesicles. Nat. Rev. Mol. Cell. Biol. 23 (5), 369–382. doi:10.1038/s41580-022-00460-3

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Keywords: allergy, autoimmunity, biotherapeutics, cancer, exosomes, extracellular vesicles, immunomodulation

Citation: Bryniarski K, Fernández-Messina L, Askenase PW and Nazimek K (2023) Editorial: Extracellular vesicles as potent modulators of immunity. Front. Cell Dev. Biol. 11:1278498. doi: 10.3389/fcell.2023.1278498

Received: 16 August 2023; Accepted: 21 August 2023;
Published: 28 August 2023.

Edited and reviewed by:

Ramani Ramchandran, Medical College of Wisconsin, United States

Copyright © 2023 Bryniarski, Fernández-Messina, Askenase and Nazimek. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Krzysztof Bryniarski, mmbrynia@cyf-kr.edu.pl, krzysztof.bryniarski@uj.edu.pl

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.