Plasma extracellular vesicle surface-located GAS6/PROS1 and CD39/CD73 attenuate inflammation
Summary: Herein, we demonstrate that extracellular vesicles (EVs) present in healthy human plasma regulate macrophage activation by triggering MERTK-dependent signaling in a growth arrest-specific 6 (GAS6)- and protein S (PROS1)-dependent manner. Moreover, EVs regulate oxidative burst and degranulat...
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| Language: | English |
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Elsevier
2025-08-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725008678 |
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| author | Martina P. Fabiano Alan M. Adamczyk Olesia A. Gololobova Ignacio G. Mazzitelli María L. Leicaj Tomás M. Grosso Paula S. Pérez Cora L. Alvarez Julieta Schachter Silvina Palmer Florencia Sabbione Fernando A. Erra Díaz Analía S. Trevani Manuel Varas-Godoy Eugenio A. Carrera Silva Kenneth W. Witwer Matías Ostrowski |
| author_facet | Martina P. Fabiano Alan M. Adamczyk Olesia A. Gololobova Ignacio G. Mazzitelli María L. Leicaj Tomás M. Grosso Paula S. Pérez Cora L. Alvarez Julieta Schachter Silvina Palmer Florencia Sabbione Fernando A. Erra Díaz Analía S. Trevani Manuel Varas-Godoy Eugenio A. Carrera Silva Kenneth W. Witwer Matías Ostrowski |
| author_sort | Martina P. Fabiano |
| collection | DOAJ |
| description | Summary: Herein, we demonstrate that extracellular vesicles (EVs) present in healthy human plasma regulate macrophage activation by triggering MERTK-dependent signaling in a growth arrest-specific 6 (GAS6)- and protein S (PROS1)-dependent manner. Moreover, EVs regulate oxidative burst and degranulation in neutrophils and the PAMP-stimulated secretion of the pro-inflammatory cytokine interleukin (IL)-1β while enhancing the secretion of the anti-inflammatory cytokine transforming growth factor beta (TGF-β). Neutrophil regulation is mediated by the biochemical activity of the EV-exposed extracellular nucleotidases CD39 and CD73, which degrade inflammatory extracellular ATP into anti-inflammatory adenosine. In turn, adenosine modulates neutrophil oxidative burst by acting through the A2A receptor. Additionally, we demonstrate that the incubation of live neutrophils with EVs enhances their interaction with macrophages, resulting in the formation of neutrophil-macrophage conjugates and the modulation of the macrophage response to an inflammatory stimulus. In conclusion, we propose that EVs from plasma serve as homeostatic regulators of inflammation by acting on multiple immune cell populations through distinct regulatory mechanisms. |
| format | Article |
| id | doaj-art-6b6f16921e694ba9bb5a89aaa49e8459 |
| institution | DOAJ |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-6b6f16921e694ba9bb5a89aaa49e84592025-08-20T02:52:37ZengElsevierCell Reports2211-12472025-08-0144811609610.1016/j.celrep.2025.116096Plasma extracellular vesicle surface-located GAS6/PROS1 and CD39/CD73 attenuate inflammationMartina P. Fabiano0Alan M. Adamczyk1Olesia A. Gololobova2Ignacio G. Mazzitelli3María L. Leicaj4Tomás M. Grosso5Paula S. Pérez6Cora L. Alvarez7Julieta Schachter8Silvina Palmer9Florencia Sabbione10Fernando A. Erra Díaz11Analía S. Trevani12Manuel Varas-Godoy13Eugenio A. Carrera Silva14Kenneth W. Witwer15Matías Ostrowski16Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina; Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, ArgentinaInstituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina; Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, ArgentinaDepartment of Comparative and Molecular Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USAInstituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina; Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, ArgentinaInstituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, ArgentinaInstituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, ArgentinaInstituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, ArgentinaInstituto de Química y Físico-Química Biológicas “Prof. Alejandro C. Paladini,” Universidad de Buenos Aires (UBA), CONICET, Buenos Aires, ArgentinaInstituto de Química y Físico-Química Biológicas “Prof. Alejandro C. Paladini,” Universidad de Buenos Aires (UBA), CONICET, Buenos Aires, ArgentinaServicio de Hematología, Hospital Británico, Buenos Aires, ArgentinaLaboratorio de inmunidad innata, Instituto de Medicina Experimental (IMEX)—CONICET, Academia Nacional de Medicina (ANM), Buenos Aires, Argentina; Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, ArgentinaInstituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina; Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, ArgentinaLaboratorio de inmunidad innata, Instituto de Medicina Experimental (IMEX)—CONICET, Academia Nacional de Medicina (ANM), Buenos Aires, Argentina; Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, ArgentinaCancer Cell Biology Lab, CEBICEM, Facultad de Ciencias, Universidad San Sebastián, Santiago, Chile; Centro Ciencia & Vida, Fundación Ciencia & Vida, Santiago, ChileLaboratorio de Trombosis Experimental e Inmunobiología de la Inflamación, IMEX, CONICET, ANM, Ciudad de Buenos Aires, ArgentinaDepartment of Comparative and Molecular Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; The Richman Family Precision Medicine Center of Excellence in Alzheimer’s Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Corresponding authorInstituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina; Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina; Corresponding authorSummary: Herein, we demonstrate that extracellular vesicles (EVs) present in healthy human plasma regulate macrophage activation by triggering MERTK-dependent signaling in a growth arrest-specific 6 (GAS6)- and protein S (PROS1)-dependent manner. Moreover, EVs regulate oxidative burst and degranulation in neutrophils and the PAMP-stimulated secretion of the pro-inflammatory cytokine interleukin (IL)-1β while enhancing the secretion of the anti-inflammatory cytokine transforming growth factor beta (TGF-β). Neutrophil regulation is mediated by the biochemical activity of the EV-exposed extracellular nucleotidases CD39 and CD73, which degrade inflammatory extracellular ATP into anti-inflammatory adenosine. In turn, adenosine modulates neutrophil oxidative burst by acting through the A2A receptor. Additionally, we demonstrate that the incubation of live neutrophils with EVs enhances their interaction with macrophages, resulting in the formation of neutrophil-macrophage conjugates and the modulation of the macrophage response to an inflammatory stimulus. In conclusion, we propose that EVs from plasma serve as homeostatic regulators of inflammation by acting on multiple immune cell populations through distinct regulatory mechanisms.http://www.sciencedirect.com/science/article/pii/S2211124725008678CP: Immunology |
| spellingShingle | Martina P. Fabiano Alan M. Adamczyk Olesia A. Gololobova Ignacio G. Mazzitelli María L. Leicaj Tomás M. Grosso Paula S. Pérez Cora L. Alvarez Julieta Schachter Silvina Palmer Florencia Sabbione Fernando A. Erra Díaz Analía S. Trevani Manuel Varas-Godoy Eugenio A. Carrera Silva Kenneth W. Witwer Matías Ostrowski Plasma extracellular vesicle surface-located GAS6/PROS1 and CD39/CD73 attenuate inflammation Cell Reports CP: Immunology |
| title | Plasma extracellular vesicle surface-located GAS6/PROS1 and CD39/CD73 attenuate inflammation |
| title_full | Plasma extracellular vesicle surface-located GAS6/PROS1 and CD39/CD73 attenuate inflammation |
| title_fullStr | Plasma extracellular vesicle surface-located GAS6/PROS1 and CD39/CD73 attenuate inflammation |
| title_full_unstemmed | Plasma extracellular vesicle surface-located GAS6/PROS1 and CD39/CD73 attenuate inflammation |
| title_short | Plasma extracellular vesicle surface-located GAS6/PROS1 and CD39/CD73 attenuate inflammation |
| title_sort | plasma extracellular vesicle surface located gas6 pros1 and cd39 cd73 attenuate inflammation |
| topic | CP: Immunology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725008678 |
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