SAR405 Several recent reviews have appeared covering differe

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 SAR405 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. Interestingly, anti-inflammatory actions for sPLA2-V were also described in mice a few years ago in a model of autoimmune complex mediated arthritis [148]. A novel mechanism was delineated, whereby sPLA2-V promotes phagocytosis of immune complexes by macrophages to ameliorate inflammation in autoimmune inflammatory arthritis. This function of sPLA2-V appears to strikingly depend on enzymatic activity [148].