The Trojan Horse of Inflammation: Extracellular Vesicles and their Functionally Active Receptors

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Abstract Extracellular vesicles (EVs) play a crucial role in intercellular communication by transferring bioactive molecules, including proteins, lipids, nucleic acids, and small metabolites, 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. In this study, we investigated the effects of EV fusion on cellular responses to inflammatory signaling. We found that the fusion renders non-responsive cells susceptible to inflammatory signaling, as evidenced by increased NF-κB activation and the release of inflammatory mediators. Our results further show that STXBP1 is essential for the merge and activation of intracellular signaling. Subsequent analysis revealed 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-kB. While receptor antagonists were unable to inhibit NF-kB activation, blocking of the fusion between EVs and their target cells with heparin mitigated inflammation in mice challenged with EVs. Together, our findings highlight EVs as important mediators for the inductions of systemic inflammatory reactions.

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