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  • First of all it should be emphasized that


    First of all, it should be emphasized that, although cPLA2α manifests a marked selectivity for phospholipids that contain AA at the sn-2 position, this does not mean in any way that, in cells, the enzyme cannot hydrolyze other fatty acyl residues to a significant extent even if this occurs at a lower rate [24]. This points out the importance of cellular compartmentalization in the regulation of biological activity, i.e. the phospholipid fatty Methotrexate composition of the membrane to which the enzyme translocates during cell activation. In this regard, it has been recently shown that cPLA2α is not only instrumental in effecting AA mobilization for eicosanoid production during inflammation reactions, but also regulates membrane phospholipid remodeling leading to Methotrexate the formation of phospholipid molecules with defined composition that participate in the execution of other responses such as generation of reactive oxygen species and secretion of bactericidal hydrolases [54]. One of such molecules is an unusual PI species which contains arachidonate at both the sn-1 and sn-2 positions of glycerol [55,56]. In addition to its biological roles in innate immune reactions mentioned above [54], this is a short-lived species that may also act as a transient acceptor for the incorporation of arachidonic acid into various cellular phospholipid classes [56]. Owing to its high arachidonic acid content, PI is also a major source for the release of this fatty acid via cPLA2α in activated immune cells [55,57]. In vitro studies suggest that cPLA2α does not show clear preference for the headgroup present at the sn-3 position, although a slight preference for zwitterionic phospholipids such as PC and PE has recently been pointed out [24]. In this regard, mass spectrometry analyses of glycerophospholipid hydrolysis during macrophage activation by phagocytic stimuli have unveiled links between the hydrolysis of either AA-containing PC or -PE and the formation of specific eicosanoid molecules [57]. During macrophage phagocytosis, the bulk of AA lost from membranes appears to originate from PC and PI, with seemingly little or no contribution from PE [57]. However, use of an inhibitor of CoA-IT that blocks the transfer of AA from PC to PE results in highly significant losses of AA from PE, indicating that during stimulation conditions AA is hydrolyzed from PE and the pools are rapidly replenished with AA from PC via transacylation reactions mediated by CoA-IT. Importantly, under these inhibitory conditions, the production of lipoxygenase metabolites increases, suggesting that the process of AA transfer between phospholipid classes does regulate the production of specific eicosanoids [57]. This opens the intriguing question of whether the synthesis of different eicosanoids is regulated by the action of cPLA2α on different phospholipid pools, and whether the different accessibility of cPLA2α to such pools can modify the course of the inflammatory response. In studies on the cPLA2α-regulated eicosanoid response of bone marrow-derived mast cells, it was found that maturation of these cells is associated with phospholipid remodeling regulated in part by cPLA2α, leading to a general decrease in AA-containing PC and PE. During the process of mast cell maturation in co-culture with fibroblasts, the AA released from mast cells by cPLA2α is transferred to adjacent fibroblasts for the synthesis of anti-allergic prostaglandin E2 [58]. The wide range of biological roles attributed to cPLA2α has been extended by recent work implicating this enzyme in the selective production of lipid mediators during macrophage polarization to either M1 (pro-inflammatory) or M2 (anti-inflammatory) states. A recent study investigated the synthesis of lipid mediators released by macrophages treated with GM-CSF or M-CSF, which polarize the cells to M1 and M2 states, respectively [59]. While under unstimulated conditions both types of macrophages generate pro-resolving lipid mediators in a similar manner, upon cell stimulation with bacteria, M2 macrophages mobilize larger amounts of AA via increased cPLA2α activation, and generate more leukotriene C4, resembling in this regard the M2-like cells in lung allergy [59]. These differences may be due, at least in part, to differences in the localization/compartmentalization of AA-metabolizing enzymes, which determine substrate accessibility. Consistent with these results, more recent work has also highlighted the different lipid mediator signatures of macrophages responding to bacteria, depending on whether they have been polarized to M1 or M2 [60]. Still, much work remains to be carried out to clarify the compartmentalized regulation of enzymes participating in the synthesis of these lipid mediators, including cPLA2α.