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  • Another important new result that has expanded


    Another important new result that has expanded the range of functions of iPLA2-VIA in physiology and pathophysiology is its implication in macrophage polarization under stimulation conditions. Ashley et al. [129] described in peritoneal macrophages from Pla2g6−/− mice that the absence of iPLA2-VIA facilitates macrophage polarization towards an anti-inflammatory M2 state, and modulates the expression of several enzymes involved in the synthesis of eicosanoid and reactive oxygen species. Conversely, the activation of genes involved in polarization to a pro-inflammatory M1 state is blunted in Pla2g6−/− macrophages. Overall, these results support a scenario where macrophage polarization may be dependent on signaling lipid molecules generated by PLA2s [129]. Regarding novel roles for iPLA2-IVA in metabolism, Deng et al. [130] recently demonstrated in Pla2g6−/− mice that the lack of the enzyme protects genetic obese mice from obesity and hepatic steatosis. The data support the notion that iPLA2-VIA has a pathophysiological function via phospholipid remodeling which ultimately results in the depletion of polyunsaturated fatty acids from PC and PE, especially those molecular species that carry palmitic or stearic acids at the sn-1 position. Inactivation of iPLA2-VIA reverses remodeling and establishes the return to normal homeostasis [130].
    An abundant body of work dating back from the 90's has documented the involvement of sPLA2-V in AA mobilization and attendant eicosanoid production [131]. In general terms, sPLA2-V acts by amplifying the action of cPLA2α, which is the key enzyme in the process, via activity-dependent or -independent mechanisms. sPLA2-V shows no clear fatty Kif15-IN-1 preference [24], and is able to release other fatty acids from cells, e.g. oleic acid or linoleic acid [[132], [133], [134]], with regulatory features that are strikingly similar to those of AA release. From these results it can be inferred that sPLA2-V may also be implicated in lipid metabolic pathways distinct from canonical AA signaling to exert its biological actions in vivo. Several recent reviews have appeared covering different aspects of the sPLA2 family of enzymes, including sPLA2-V, and the interested reader is kindly directed to these for specific details [34,[135], [136], [137]]. It is important to remark here, however, that recent studies on sPLA2-V suggest that some of the biological functioning of the enzyme is context- and even species-specific [34]. This is an important concept to take into account, because a considerable part of results regarding the role of sPLA2-V in pathophysiology have come from studies in mice, and the availability of the sPLA2-V knockout mouse model has provided much valuable insight [46,138]. However, the human enzyme differs from the mouse enzyme in at least one key aspect. In mouse peritoneal macrophages, sPLA2-V translocates to the phagosome after ingestion of zymosan and regulates phagocytosis by mechanisms that may or may not depend on eicosanoid synthesis [139,140]. Under similar experimental conditions, however, the enzyme does not translocate to the phagosome in humans [61,62]. These data suggest that, at least in humans, the regulatory actions of the enzyme on the phagocytosis process itself occur at a level distinct from that of the phagosome, perhaps at the plasma membrane level. Interestingly however, it was recognized that the regulation of phagocytosis by sPLA2-V in human and murine cells may actually lead to similar outcomes, i.e. in both systems sPLA2-V favors the phagocytosis process, thus helps to resolve inflammation [[139], [140], [141]]. A recent lipidomic analysis determined that the increased expression of sPLA2-V in interleukin-4–treated macrophages is selectively linked to increased levels of cellular ethanolamine lysophospholipids (LPE) [141]. These lipid molecules are necessary to support the elevated phagocytic response that these cells exhibit in response to both zymosan particles and live bacteria. The addition of exogenous LPE fully restores phagocytosis in sPLA2-V–deficient cells, and overexpression of the enzyme produces a significant increase of the phagocytic capacity of the cells. It is possible that sPLA2-V acts on the plasma membrane, and the accumulation of LPE alters the structure and fluidity of a variety of microdomains, including lipid rafts, favoring oligomerization/interaction of phagocytic receptors. Thus LPE may help develop further signaling, eventually favoring repair mechanisms and the return to homeostasis (Fig. 2). It has recently been discovered that ethanolamine lysoplasmalogens are, among LPE molecular species, the ones producing the largest effect (J. Rubio and J. Balsinde, unpublished data), pointing out again the importance of specific lipids in regulating innate immune functions. It is worth mentioning in this regard that another member of the sPLA2 family, sPLA2-IIF, was described earlier to cleave ethanolamine plasmalogens, generating lysoplasmalogen in keratinocytes, which is a biomarker of skin diseases [142]. Since ethanolamine phospholipids reside primarily in the inner leaflet of the plasma membrane, a scenario such as the one described above would be fully consistent with the large body of literature indicating that, after secretion of sPLA2-V to the extracellular medium, the enzyme re-associates with the plasma membrane and, subsequently, is re-internalized by different mechanisms, including interaction of the enzyme with heparan sulfate proteoglycans [143] or caveolin-rich domains [144,145]. This could bring the enzyme into proximity with ethanolamine phospholipid pools at the inner leaflet to regulate specific cellular responses (Fig. 2) [131,146,147]. Thus, sPLA2-V may act in an autocrine or paracrine fashion at different subcellular locations in the cell, depending on cell type and the nature of the activating stimulus.