Ement of PMN recruitment and the impediment of wound healing partly because of their surface-bound MPO and pro-inflammatory miR-23a and miR-155 content [102,108,111]. Fewer studies investigated the nature of PMN-EVs released upon LPS stimulation. Interestingly, in contrast to fMLP, LPS triggered pro-inflammatory EVs. Habhab et al. examined splenocytes (predominantly neutrophils)-derived EVs and found pro-inflammatory, pro-coagulant and pro-senescent responses in endothelial cells via redox-sensitive pathways [114]. LPS-triggered exosomes enhanced equine airway smooth muscle cell proliferation [115] and combined LPS and fMLP activation induced EVs enhanced the phagocytosis plus the ROS production of monocytes and resting neutrophils [113]. 2.two.three. Effect of PMN-EVs Released upon Stimulation with Endogenous Pro-Inflammatory Mediators PMN priming or activation can also be feasible with various cytokines like TNF-, IFN-, GM-CSF, C5a, PAF and IL-8. PMN-EVs from cells activated by either PAF [97] or IL-8 [96] demonstrated anti-inflammatory prospective by decreasing PMN recruitment [97], as well as NK cell [96] activation. C5a-induced EVs had been rated as anti-inflammatory vesicles as they inhibited macrophage maturation [94]; however, a recently published work showed an opposite impact where C5a-triggered EVs activated resting neutrophils to generate ROS and induced IL-6 secretion [121]. EVs released from TNF–stimulated PMNs exhibit a pro-inflammatory profile: they improve the pro-inflammatory cytokine production and adhesion molecule expression of HUVEC [137] and contribute to genomic SARS-CoV-2 NSP7 Proteins Synonyms instability, inflammation as well as the impediment of wound healing in intestinal epithelial cells. These latter functions have been equivalent inside the case of the powerful inflammatory signal transmitting IFN- and GM-CSF-triggered EVs [102]. Kahn et al. described that TNF–induced EVs transfer functional kinin B1 -receptors to human embryonic kidney cells and induce calcium influx soon after stimulation [119]. In contrast, the group of Perretti reported the anti-inflammatory impact of TNF–triggered PMN-EVs on human monocyte-derived macrophages and also a macrophage-fibroblast-like synoviocyte co-culture system [118]. 2.two.four. Effect of PMN-EVs Released upon Stimulation with Pathogens Opsonized pathogens represent the strongest all-natural activating signal to PMN by means of PRR (pattern recognition receptor) and opsonin receptors (e.g., Mac-1/CR3, FcRs). Our group showed that PMN-EVs released after stimulation with opsonized zymosan carry a highly effective pro-inflammatory possible by enhancing ROS production and IL-8 release of resting PMNs and HUVEC [86]. Yet another group also discovered pro-inflammatory effects of bacteria and EV EphA3 Proteins manufacturer aggregates manifesting in enhanced IL-6, IL-1 production and higher CD86 and HLA-DR expression of macrophages [144]. Nonetheless, this study emphasized the role of aggregated bacteria in the detected pro-inflammatory effects, as EVs alone did not boost the cytokine release of macrophages. Alvarez-Jim ez et al. also described a pro-inflammatory profile of PMN-EVs released following M. tuberculosis infection of neutrophils [105]. On the contrary, Duarte et al. reported diminished bacterial clearance by human monocyte-derived macrophages soon after treating them with PMN-EVs released following M. tuberculosis infection [85]. The difference in outcome from the latter two publications may be explained by the differences inside the MOI (multiplicity of infection) for neutrophilCells 2020, 9,12 ofinfection, the time.