Papareddy et al. demonstrated that extracellular vesicles (EVs) from activated immune cells carried inflammatory receptor agonist complexes and adaptor proteins for mediating intracellular signaling. Upon STXBP1-dependent fusion with target cells, EVs unloaded their cytosolic cargo and translocated their surface proteins, inducing NF-κB activation and the release of inflammatory mediators in both immune and non-immune target cells. Receptor antagonists did not effectively inhibit NF-κB activation, but using heparin to block the fusion between EVs and target cells limited EV-induced systemic inflammation in mice.
Contributed by Lauren Hitchings
ABSTRACT: Extracellular vesicles (EVs) play a crucial role in intercellular communication by transferring bioactive molecules from donor to recipient cells. As a result, EV fusion leads to the modulation of cellular functions and has an impact on both physiological and pathological processes in the recipient cell. This study explores the impact of EV fusion on cellular responses to inflammatory signaling. Our findings reveal that fusion renders non-responsive cells susceptible to inflammatory signaling, as evidenced by increased NF-κB activation and the release of inflammatory mediators. Syntaxin-binding protein 1 is essential for the merge and activation of intracellular signaling. Subsequent analysis show that EVs transfer their functionally active receptors to target cells, making them prone to an otherwise unresponsive state. EVs in complex with their agonist, require no further stimulation of the target cells to trigger mobilization of NF-κB. While receptor antagonists were unable to inhibit NF-κB activation, blocking of the fusion between EVs and their target cells with heparin mitigated inflammation in mice challenged with EVs.
Author Info: (1) Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden. praveen.papareddy@med.lu.se. (2) Division of Infection Medicine, Department of C
Author Info: (1) Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden. praveen.papareddy@med.lu.se. (2) Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden. SMATHERIA gGmbH - Non-Profit Biomedical Research Institute, Hannover, Germany. Center for Systems Neuroscience (ZSN), Hannover, Germany. (3) Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden. Department of Viroscience, Erasmus Medical Center, Rotterdam, the Netherlands. (4) Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden. (5) Section of Surgery, Department of Clinical Sciences, Lund University, Malm, Sweden. (6) Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden. (7) Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden. (8) Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden. (9) Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden. (10) Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden. (11) Division of Oncology and Pathology, Lund, Department of Clinical Sciences, Lund University, Lund, Sweden. (12) Division of Infection Medicine, Helsingborg Hospital and Department of Clinical Sciences Helsingborg, Lund University, Lund, Sweden. (13) Section of Surgery, Department of Clinical Sciences, Lund University, Malm, Sweden. (14) Division of Infection Medicine, Helsingborg Hospital and Department of Clinical Sciences Helsingborg, Lund University, Lund, Sweden. (15) Department of Infectious Diseases, First Faculty of Medicine, Charles University and Military University Hospital Prague, Praha, Czech Republic. (16) Department of Infectious Diseases, First Faculty of Medicine, Charles University and Military University Hospital Prague, Praha, Czech Republic. (17) Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden. heiko.hewald@med.lu.se.
