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.

Center for Systems Neuroscience Hannover Germany

Department of Infectious Diseases 1st Faculty of Medicine Charles University and Military University Hospital Prague Praha Czech Republic

Department of Viroscience Erasmus Medical Center Rotterdam the Netherlands

Division of Infection Medicine Department of Clinical Sciences Lund University Lund Sweden

Division of Infection Medicine Helsingborg Hospital and Department of Clinical Sciences Helsingborg Lund University Lund Sweden

Division of Oncology and Pathology Lund Department of Clinical Sciences Lund University Lund Sweden

Section of Surgery Department of Clinical Sciences Lund University Malmö Sweden

SMATHERIA gGmbH Non Profit Biomedical Research Institute Hannover Germany

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Talamonti G, D’Aliberti G, Cenzato M. Aulus cornelius celsus and the head injuries. World Neurosurg. 2020;133:127–134. doi: 10.1016/j.wneu.2019.09.119. PubMed DOI

Huber-Lang M, Lambris JD, Ward PA. Innate immune responses to trauma. Nat. Immunol. 2018;19:327–341. doi: 10.1038/s41590-018-0064-8. PubMed DOI PMC

Chousterman BG, Swirski FK, Weber GF. Cytokine storm and sepsis disease pathogenesis. Semin. Immunopathol. 2017;39:517–528. doi: 10.1007/s00281-017-0639-8. PubMed DOI

Hoesel B, Schmid JA. The complexity of NF-kappaB signaling in inflammation and cancer. Mol. Cancer. 2013;12:86. doi: 10.1186/1476-4598-12-86. PubMed DOI PMC

Frohlich, M. et al. Temporal phenotyping of circulating microparticles after trauma: a prospective cohort study. Scand. J. Trauma Resusc. Emerg. Med26, 33 (2018). PubMed PMC

Boscolo A, et al. Levels of circulating microparticles in septic shock and sepsis-related complications: a case-control study. Minerva Anestesiol. 2019;85:625–634. doi: 10.23736/S0375-9393.18.12782-9. PubMed DOI

Sabatier F, et al. Interaction of endothelial microparticles with monocytic cells in vitro induces tissue factor-dependent procoagulant activity. Blood. 2002;99:3962–3970. doi: 10.1182/blood.V99.11.3962. PubMed DOI

Burger D, et al. Microparticles: biomarkers and beyond. Clin. Sci. (Lond.) 2013;124:423–441. doi: 10.1042/CS20120309. PubMed DOI

Cognasse F, et al. The role of microparticles in inflammation and transfusion: A concise review. Transfus. Apher. Sci. 2015;53:159–167. doi: 10.1016/j.transci.2015.10.013. PubMed DOI

Rizo J, Sudhof TC. Snares and Munc18 in synaptic vesicle fusion. Nat. Rev. Neurosci. 2002;3:641–653. doi: 10.1038/nrn898. PubMed DOI

Atai NA, et al. Heparin blocks transfer of extracellular vesicles between donor and recipient cells. J. Neurooncol. 2013;115:343–351. doi: 10.1007/s11060-013-1235-y. PubMed DOI PMC

Shen C, et al. The trans-SNARE-regulating function of Munc18-1 is essential to synaptic exocytosis. Nat. Commun. 2015;6:8852. doi: 10.1038/ncomms9852. PubMed DOI PMC

Yu H, et al. SNARE zippering requires activation by SNARE-like peptides in Sec1/Munc18 proteins. Proc. Natl Acad. Sci. USA. 2018;115:E8421–e8429. doi: 10.1073/pnas.1802645115. PubMed DOI PMC

Mause SF, Weber C. Microparticles: protagonists of a novel communication network for intercellular information exchange. Circ. Res. 2010;107:1047–1057. doi: 10.1161/CIRCRESAHA.110.226456. PubMed DOI

De Paoli SH, et al. Dissecting the biochemical architecture and morphological release pathways of the human platelet extracellular vesiculome. Cell Mol. Life Sci. 2018;75:3781–3801. doi: 10.1007/s00018-018-2771-6. PubMed DOI PMC

Chimen M, et al. Appropriation of GPIbalpha from platelet-derived extracellular vesicles supports monocyte recruitment in systemic inflammation. Haematologica. 2020;105:1248–1261. doi: 10.3324/haematol.2018.215145. PubMed DOI PMC

Prescott JA, Mitchell JP, Cook SJ. Inhibitory feedback control of NF-kappaB signalling in health and disease. Biochem J. 2021;478:2619–2664. doi: 10.1042/BCJ20210139. PubMed DOI PMC

Kadkova A, Radecke J, Sorensen JB. The SNAP-25 Protein Family. Neuroscience. 2019;420:50–71. doi: 10.1016/j.neuroscience.2018.09.020. PubMed DOI

Oehmcke S, et al. Stimulation of blood mononuclear cells with bacterial virulence factors leads to the release of pro-coagulant and pro-inflammatory microparticles. Cell Microbiol. 2012;14:107–119. doi: 10.1111/j.1462-5822.2011.01705.x. PubMed DOI

Verhage M, et al. Synaptic assembly of the brain in the absence of neurotransmitter secretion. Science. 2000;287:864–869. doi: 10.1126/science.287.5454.864. PubMed DOI

Wada K, Hosokawa K, Ito Y, Maeda M. Effects of ROCK inhibitor Y-27632 on cell fusion through a microslit. Biotechnol. Bioeng. 2015;112:2334–2342. doi: 10.1002/bit.25641. PubMed DOI

Futosi K, Fodor S, Mocsai A. Neutrophil cell surface receptors and their intracellular signal transduction pathways. Int. Immunopharmacol. 2013;17:638–650. doi: 10.1016/j.intimp.2013.06.034. PubMed DOI PMC

Verstrepen L, et al. TLR-4, IL-1R and TNF-R signaling to NF-kappaB: variations on a common theme. Cell Mol. Life Sci. 2008;65:2964–2978. doi: 10.1007/s00018-008-8064-8. PubMed DOI PMC

Casella JF, Flanagan MD, Lin S. Cytochalasin D inhibits actin polymerization and induces depolymerization of actin filaments formed during platelet shape change. Nature. 1981;293:302–305. doi: 10.1038/293302a0. PubMed DOI

Wen PJ, et al. Actin dynamics provides membrane tension to merge fusing vesicles into the plasma membrane. Nat. Commun. 2016;7:12604. doi: 10.1038/ncomms12604. PubMed DOI PMC

Kowal J, Tkach M, Thery C. Biogenesis and secretion of exosomes. Curr. Opin. Cell Biol. 2014;29:116–125. doi: 10.1016/j.ceb.2014.05.004. PubMed DOI

Picca A, et al. Extracellular vesicles and damage-associated molecular patterns: a Pandora’s box in health and disease. Front. Immunol. 2020;11:601740. doi: 10.3389/fimmu.2020.601740. PubMed DOI PMC

Hung Y, et al. The exosomal compartment protects epidermal growth factor receptor from small molecule inhibitors. Biochem. Biophys. Res Commun. 2019;510:42–47. doi: 10.1016/j.bbrc.2018.12.187. PubMed DOI

Jiang CY, et al. The potential role of circulating exosomes in protecting myocardial injury in acute myocardial infarction via regulating miR-190a-3p/CXCR4/CXCL12 pathway. J. Bioenerg. Biomembr. 2022;54:175–189. doi: 10.1007/s10863-022-09944-5. PubMed DOI

Zeng F, Morelli AE. Extracellular vesicle-mediated MHC cross-dressing in immune homeostasis, transplantation, infectious diseases, and cancer. Semin Immunopathol. 2018;40:477–490. doi: 10.1007/s00281-018-0679-8. PubMed DOI PMC

Johnston A, et al. A systematic review of clinical practice guidelines on the use of low molecular weight heparin and fondaparinux for the treatment and prevention of venous thromboembolism: Implications for research and policy decision-making. PLoS One. 2018;13:e0207410. doi: 10.1371/journal.pone.0207410. PubMed DOI PMC

Kearon C, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of American College of chest physicians evidence-based clinical practice guidelines. Chest. 2012;141:e419S–e496S. doi: 10.1378/chest.11-2301. PubMed DOI PMC

Hull RD. Treatment of pulmonary embolism: The use of low-molecular-weight heparin in the inpatient and outpatient settings. Thromb. Haemost. 2008;99:502–510. doi: 10.1160/TH07-08-0500. PubMed DOI

Shore-Lesserson L, et al. The society of thoracic surgeons, the society of cardiovascular anesthesiologists, and the american society of extracorporeal technology: clinical practice guidelines-anticoagulation during cardiopulmonary bypass. Ann. Thorac. Surg. 2018;105:650–662. doi: 10.1016/j.athoracsur.2017.09.061. PubMed DOI

Mousavi S, Moradi M, Khorshidahmad T, Motamedi M. Anti-Inflammatory Effects of Heparin and Its Derivatives: A Systematic Review. Adv. Pharm. Sci. 2015;2015:507151. PubMed PMC

Borsig L. Heparin as an inhibitor of cancer progression. Prog. Mol. Biol. Transl. Sci. 2010;93:335–349. doi: 10.1016/S1877-1173(10)93014-7. PubMed DOI

Qiu M, et al. Pharmacological and clinical application of heparin progress: An essential drug for modern medicine. Biomed. Pharmacother. 2021;139:111561. doi: 10.1016/j.biopha.2021.111561. PubMed DOI

Gong J, Jaiswal R, Dalla P, Luk F, Bebawy M. Microparticles in cancer: A review of recent developments and the potential for clinical application. Semin. Cell Dev. Biol. 2015;40:35–40. doi: 10.1016/j.semcdb.2015.03.009. PubMed DOI

Rosell A, et al. Patients with COVID-19 have elevated levels of circulating extracellular vesicle tissue factor activity that is associated with severity and mortality-brief report. Arterioscler Thromb. Vasc. Biol. 2021;41:878–882. doi: 10.1161/ATVBAHA.120.315547. PubMed DOI PMC

Ayerbe L, Risco C, Ayis S. The association between treatment with heparin and survival in patients with Covid-19. J. Thromb. Thrombolysis. 2020;50:298–301. doi: 10.1007/s11239-020-02162-z. PubMed DOI PMC

Miesbach W, Makris M. COVID-19: coagulopathy, risk of thrombosis, and the rationale for anticoagulation. Clin. Appl Thromb. Hemost. 2020;26:1076029620938149. doi: 10.1177/1076029620938149. PubMed DOI PMC

Xia, B. et al. Extracellular vesicles mediate antibody-resistant transmission of SARS-CoV-2. Cell Discov. 9, 2 (2023). PubMed PMC

Abraham E, et al. Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. JAMA. 1995;273:934–941. doi: 10.1001/jama.1995.03520360048038. PubMed DOI

Fisher CJ, Jr, et al. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA. 1994;271:1836–1843. doi: 10.1001/jama.1994.03510470040032. PubMed DOI