Over the last 20 years, extracellular vesicles (EVs) have been established as an additional way to transmit signals outside the cell. that EVs may carry and deliver membrane-derived bioactive lipids that play an important function in the immune system and related pathologies, such as prostaglandins, leukotrienes, specialized pro-resolving mediators, and lysophospholipids. EVs protect bioactive lipids from degradation and play a role in the transcellular synthesis of prostaglandins and leukotrienes. Here, we summarized the part of EVs in the rules of immune response, specifically focusing our attention within the growing part of EVs as service providers of bioactive lipids, which is definitely important for immune system function. [50,57], they include mycobacterial parts. Beyond developing an antigen-specific response, these EVs when incubated with na?ve macrophage enhance the launch of proinflammatory cytokines and chemokines, and Nutlin 3a inhibition promote the recruitment of other immune cells, as a result prompting granuloma formation [58,59]. Similar results were acquired when macrophages were infected with parasites . Macrophage EVs have also been involved in the activation of inflammatory reactions associated with vascular swelling and atherosclerosis. Nfatc1 Specifically, it has been demonstrated that EVs released by macrophages promote leukocyte migration from the upregulation of intracellular adhesion molecule (ICAM-1) , participating in the regulatory network that prompts wall infiltration. Besides, macrophage EVs have been shown to impact endothelial cell (EC) function by regulating integrin trafficking . The release of EVs from additional immune cells has also been demonstrated to affect the function of ECs. In the case of EVs released by Nutlin 3a inhibition neutrophilic granulocytes, a pro-inflammatory part towards ECs was indicated by the evidence that these vesicles Nutlin 3a inhibition stimulate the EC secretion of the pro-inflammatory cytokine IL6 and induce myeloperoxidase-mediated EC damage [63,64]. However, the relationships between immune cells and vascular cells is definitely complex, and there is evidence that EVs from different blood sources may have different Nutlin 3a inhibition actions on ECs, enhancing or inhibiting swelling . The inflammatory part of EVs released by neutrophilic granulocytes was confirmed by the finding that they possess an antibacterial effect that is selective for specific bacterial strains . However, Nutlin 3a inhibition several studies also provided evidence of an anti-inflammatory effect of these EVs through different mechanisms [67,68]. Neutrophil-derived EVs were reported to increase the secretion of the anti-inflammatory cytokine TGF-1 from monocytes, therefore interfering with the maturation of monocyte-derived DCs . They were also reported to quick the release of lipid mediators, stimulating the phagocytosis of dying cells by macrophages . In addition to neutrophilic granulocytes, additional granulocytes, such as mast cells, launch EVs with immunomodulation properties, as mast cell EVs were demonstrated to induce the maturation of DCs and the activation of and B and T lymphocytes [71,72]. EVs released by NK cells have raised considerable desire for the oncology field, as they happen to be shown to show cytotoxic activity against tumor cells and activate immune cells [73,74]. Moreover, NK cells are the target of EVs that are released by several cell types. These EVs are able to activate NK cells, conferring to them the ability to identify tumor cells and reduce their growth [75,76]. On the other hand, EVs comprising NKG2D receptor ligands were shown to downregulate NK function and reduce NK cytotoxicity, therefore favouring tumor escape [77,78]. 3. Lipids mainly because Signaling Mediators in the Immune System Lipid mediators play a pivotal part in immune signaling and inflammatory processes. Indeed, problems in the rate of metabolism of lipid mediators or in their receptors account for several inflammatory and immune disorders . With this section, we summarize probably the most relevant features of lipid mediators and their involvement in immune system signaling, in order to expose key findings about the part of EVs as conveyors of membrane-derived bioactive lipids in the next section. Based on their biosynthetic source, lipid mediators can be grouped into two different classes, i.e., polyunsaturated fatty acids (PUFA)-derived mediators and lysophospholipids, as extensively examined elsewhere . Bioactive lipids derived from PUFA can be further divided into two subclasses: lipid mediators deriving from your ?6 arachidonic acid (AA, 20:4 n6), which include thromboxanes (TGs), prostaglandins (PGs), leukotrienes (LTs), and lipoxins (LXs), and lipid mediators deriving from ?3-PUFA, i.e., E-series resolvins and D-series resolvins, protectins, and maresins. Except for LXs, lipids mediators derived from ?6-PUFA (generally known as eicosanoids) are pro-inflammatory, whereas all the mediators derived from ?3-PUFA promote the resolution of inflammation. It is noteworthy that another class of lipid mediators, i.e., endocannabinoids (eCBs), also originates from PUFA rate of metabolism, but their classification is definitely less clear, mainly because eCBs may derive from either ?6- or ?3-PUFA [80,81]. Membrane-derived bioactive lipids derived from lysophospholipids (LPLs) can be divided into lysoglycerophospholipids (LGPLs), which are characterized by glycerol as the backbone, and lysosphingophospholipids (LSLs), which are characterized by sphingosine as the backbone . 3.1. Classical Eicosanoids AA-derived eicosanoids exert a pivotal part in immune response. Cells of myeloid lineage, such as platelets,.