Extracellular vesicles from human plasma dampen inflammation and promote tissue repair functions in macrophages
Abstract Although inflammation is a vital defence response to infection, if left uncontrolled, it can lead to pathology. Macrophages are critical players both in driving the inflammatory response and in the subsequent events required for restoring tissue homeostasis. Extracellular vesicles (EVs) are...
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Format: | Article |
Language: | English |
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Wiley
2023-06-01
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Series: | Journal of Extracellular Vesicles |
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Online Access: | https://doi.org/10.1002/jev2.12331 |
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author | Alan M. Adamczyk María Luz Leicaj Martina Paula Fabiano Gonzalo Cabrerizo Nadia Bannoud Diego O. Croci Kenneth W. Witwer Federico Remes Lenicov Matías Ostrowski Paula Soledad Pérez |
author_facet | Alan M. Adamczyk María Luz Leicaj Martina Paula Fabiano Gonzalo Cabrerizo Nadia Bannoud Diego O. Croci Kenneth W. Witwer Federico Remes Lenicov Matías Ostrowski Paula Soledad Pérez |
author_sort | Alan M. Adamczyk |
collection | DOAJ |
description | Abstract Although inflammation is a vital defence response to infection, if left uncontrolled, it can lead to pathology. Macrophages are critical players both in driving the inflammatory response and in the subsequent events required for restoring tissue homeostasis. Extracellular vesicles (EVs) are membrane‐enclosed structures released by cells that mediate intercellular communication and are present in all biological fluids, including blood. Herein, we show that extracellular vesicles from plasma (pEVs) play a relevant role in the control of inflammation by counteracting PAMP‐induced macrophage activation. Indeed, pEV‐treatment of macrophages simultaneously with or prior to PAMP exposure reduced the secretion of pro‐inflammatory IL‐6 and TNF‐α and increased IL‐10 response. This anti‐inflammatory activity was associated with the promotion of tissue‐repair functions in macrophages, characterized by augmented efferocytosis and pro‐angiogenic capacity, and increased expression of VEGFa, CD300e, RGS2 and CD93, genes involved in cell growth and tissue remodelling. We also show that simultaneous stimulation of macrophages with a PAMP and pEVs promoted COX2 expression and CREB phosphorylation as well as the accumulation of higher concentrations of PGE2 in cell culture supernatants. Remarkably, the anti‐inflammatory activity of pEVs was abolished if cells were treated with a pharmacological inhibitor of COX2, indicating that pEV‐mediated induction of COX2 is critical for the pEV‐mediated inhibition of inflammation. Finally, we show that pEVs added to monocytes prior to their M‐CSF‐induced differentiation to macrophages increased efferocytosis and diminished pro‐inflammatory cytokine responses to PAMP stimulation. In conclusion, our results suggest that pEVs are endogenous homeostatic modulators of macrophages, activating the PGE2/CREB pathway, decreasing the production of inflammatory cytokines and promoting tissue repair functions. |
first_indexed | 2024-03-13T03:56:08Z |
format | Article |
id | doaj.art-a04db062d02d4c68bac7ae2f7aaf8eb0 |
institution | Directory Open Access Journal |
issn | 2001-3078 |
language | English |
last_indexed | 2024-03-13T03:56:08Z |
publishDate | 2023-06-01 |
publisher | Wiley |
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series | Journal of Extracellular Vesicles |
spelling | doaj.art-a04db062d02d4c68bac7ae2f7aaf8eb02023-06-22T05:06:00ZengWileyJournal of Extracellular Vesicles2001-30782023-06-01126n/an/a10.1002/jev2.12331Extracellular vesicles from human plasma dampen inflammation and promote tissue repair functions in macrophagesAlan M. Adamczyk0María Luz Leicaj1Martina Paula Fabiano2Gonzalo Cabrerizo3Nadia Bannoud4Diego O. Croci5Kenneth W. Witwer6Federico Remes Lenicov7Matías Ostrowski8Paula Soledad Pérez9Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS) Universidad de Buenos Aires‐CONICET Buenos Aires ArgentinaInstituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS) Universidad de Buenos Aires‐CONICET Buenos Aires ArgentinaInstituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS) Universidad de Buenos Aires‐CONICET Buenos Aires ArgentinaInstituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS) Universidad de Buenos Aires‐CONICET Buenos Aires ArgentinaLaboratorio de Glicobiología y Biología Vascular Instituto de Histología y Embriología de Mendoza CONICET‐Universidad Nacional de Cuyo Mendoza ArgentinaLaboratorio de Glicobiología y Biología Vascular Instituto de Histología y Embriología de Mendoza CONICET‐Universidad Nacional de Cuyo Mendoza ArgentinaDepartment of Molecular and Comparative Pathobiology The Johns Hopkins University School of Medicine Baltimore Maryland USAInstituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS) Universidad de Buenos Aires‐CONICET Buenos Aires ArgentinaInstituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS) Universidad de Buenos Aires‐CONICET Buenos Aires ArgentinaInstituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS) Universidad de Buenos Aires‐CONICET Buenos Aires ArgentinaAbstract Although inflammation is a vital defence response to infection, if left uncontrolled, it can lead to pathology. Macrophages are critical players both in driving the inflammatory response and in the subsequent events required for restoring tissue homeostasis. Extracellular vesicles (EVs) are membrane‐enclosed structures released by cells that mediate intercellular communication and are present in all biological fluids, including blood. Herein, we show that extracellular vesicles from plasma (pEVs) play a relevant role in the control of inflammation by counteracting PAMP‐induced macrophage activation. Indeed, pEV‐treatment of macrophages simultaneously with or prior to PAMP exposure reduced the secretion of pro‐inflammatory IL‐6 and TNF‐α and increased IL‐10 response. This anti‐inflammatory activity was associated with the promotion of tissue‐repair functions in macrophages, characterized by augmented efferocytosis and pro‐angiogenic capacity, and increased expression of VEGFa, CD300e, RGS2 and CD93, genes involved in cell growth and tissue remodelling. We also show that simultaneous stimulation of macrophages with a PAMP and pEVs promoted COX2 expression and CREB phosphorylation as well as the accumulation of higher concentrations of PGE2 in cell culture supernatants. Remarkably, the anti‐inflammatory activity of pEVs was abolished if cells were treated with a pharmacological inhibitor of COX2, indicating that pEV‐mediated induction of COX2 is critical for the pEV‐mediated inhibition of inflammation. Finally, we show that pEVs added to monocytes prior to their M‐CSF‐induced differentiation to macrophages increased efferocytosis and diminished pro‐inflammatory cytokine responses to PAMP stimulation. In conclusion, our results suggest that pEVs are endogenous homeostatic modulators of macrophages, activating the PGE2/CREB pathway, decreasing the production of inflammatory cytokines and promoting tissue repair functions.https://doi.org/10.1002/jev2.12331CREBexosomesextracellular vesicleshuman plasmainfectioninflammation |
spellingShingle | Alan M. Adamczyk María Luz Leicaj Martina Paula Fabiano Gonzalo Cabrerizo Nadia Bannoud Diego O. Croci Kenneth W. Witwer Federico Remes Lenicov Matías Ostrowski Paula Soledad Pérez Extracellular vesicles from human plasma dampen inflammation and promote tissue repair functions in macrophages Journal of Extracellular Vesicles CREB exosomes extracellular vesicles human plasma infection inflammation |
title | Extracellular vesicles from human plasma dampen inflammation and promote tissue repair functions in macrophages |
title_full | Extracellular vesicles from human plasma dampen inflammation and promote tissue repair functions in macrophages |
title_fullStr | Extracellular vesicles from human plasma dampen inflammation and promote tissue repair functions in macrophages |
title_full_unstemmed | Extracellular vesicles from human plasma dampen inflammation and promote tissue repair functions in macrophages |
title_short | Extracellular vesicles from human plasma dampen inflammation and promote tissue repair functions in macrophages |
title_sort | extracellular vesicles from human plasma dampen inflammation and promote tissue repair functions in macrophages |
topic | CREB exosomes extracellular vesicles human plasma infection inflammation |
url | https://doi.org/10.1002/jev2.12331 |
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