Abstract

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)-1? while enhancing the secretion of the anti-inflammatory cytokine transforming growth factor beta (TGF-?). 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. © 2025 The Authors