Fig. 2

Hypothetical schematic model of EV-cargo delivery to immune cells and EV-aided immune transendothelial migration. a Exomes produced by the BMEC, can deliver its cargo via cellular endocytic internalization. Conversely, microvesicle fusion with cell membranes of the target cell facilities emptying of their cargo. The contents in EVs can be highly heterogenous (in terms of composition and amount) although it’s generally recognized that proteins, genetic material, and metabolites encompass most of its components. The biological consequences that BMEC-EVs could have on immune cells remains largely unknown. However, recent evidence suggests that EVs could affect T cell activation and differentiation status. b The presence of inflammatory mediators activates the brain endothelium and results in localized blood–brain barrier instability (BBB) (1). Subsequent hyperpermeability at the BBB may be explained by the temporal production of microvesicles and exosomes (EVs) (2). Importantly, brain endothelial derived EVs are known to contain tight junction proteins in their cargo [44, 45]. Although inflammatory mediators, drugs of abuse etc., induce the biogenesis of EVs from the endothelium, we propose that only activated immune cells can efficiently use these vesicles for gaining entry into the CNS. In the case illustrated, we hypothesize activated monocytes bind EVs containing TJ proteins (3), which then allows for direct “unzipping” of intercellular tight junction complexes at the BBB (4), leading to immune cell access to the perivascular space