The role of extracellular vesicle fusion with target cells in triggering systemic inflammation

A recent study conducted by researchers at Lund University delved into the role of EVs in intercellular communication, particularly focusing on their impact on inflammatory signaling. Their findings shed light on how EV fusion with recipient cells can drastically alter cellular responses.

Imagine EVs as tiny packages, delivering important cargo from one cell to another. When they fuse with a recipient cell, they transfer bioactive molecules, influencing the cell’s behavior. This process not only affects normal physiological functions but also plays a role in various pathological processes.

The researchers discovered that when EVs fuse with non-responsive cells, these cells become more susceptible to inflammatory signaling. This was evident through increased activation of a key signaling pathway called NF-κB, which is known to regulate inflammation, and the subsequent release of inflammatory mediators.

But how does this fusion happen? It turns out that a protein called syntaxin-binding protein 1 plays a crucial role in facilitating the merge of EVs with recipient cells, activating intracellular signaling pathways in the process. Moreover, the study revealed that EVs transfer their functionally active receptors to target cells during fusion, essentially priming them to respond to inflammatory signals.

What’s even more intriguing is that once fused with their target cells, EVs can trigger NF-κB mobilization without the need for further stimulation. This means that even in the absence of external inflammatory triggers, EVs can kickstart an inflammatory response in recipient cells.

The schematic diagram shows the transfer of ligand-receptor immune complexes to the recipient cells and its importance in EV signaling

Fig. 8
Binding of LPS to a donor cell via TLR initiates intracellular signaling pathways, engaging MYD88, IRAK1/4, TRAF6, and NF-kB. Subsequently, microvesicles containing the complete signaling complex are released from the donor cell. When these microparticles bind to their target, the recipient cell can leverage the signaling complex to activate its NF-kB pathway.

The researchers tested various approaches to inhibit this inflammatory response. Surprisingly, traditional receptor antagonists were ineffective in blocking NF-κB activation. However, when they blocked the fusion between EVs and target cells using heparin, a compound known for its anticoagulant properties, they observed a significant reduction in inflammation in mice challenged with EVs.

These findings provide valuable insights into the intricate world of intercellular communication and inflammation. By understanding how EVs influence cellular responses, researchers may uncover new therapeutic strategies for managing inflammatory diseases.

In conclusion, while EVs may be tiny, their role in cellular communication and inflammation is anything but insignificant. They serve as important messengers, shaping the way cells interact and respond to their environment. As we continue to unravel the mysteries of EVs, we inch closer to unlocking new possibilities for treating inflammatory disorders and improving human health.

Papareddy P, Tapken I, Kroh K, Varma Bhongir RK, Rahman M, Baumgarten M, Cim EI, Györffy L, Smeds E, Neumann A, Veerla S, Olinder J, Thorlacus H, Ryden C, Bartakova E, Holub M, Herwald H. (2024) The role of extracellular vesicle fusion with target cells in triggering systemic inflammation. Nat Commun 15(1):1150. [article]

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