Regarding eicosanoid production iPLA VIA appears in general
Regarding eicosanoid production, iPLA2-VIA appears, in general terms, not to play a major role in mediating this response in innate immunity and inflammation, as evidenced by the large number of studies highlighting the lack of effect of selective inhibition of the enzyme in stimulus-induced AA release in multiple immune cells [45,48,57,, , , , , , , , ]. Rather, the involvement of iPLA2-VIA in the eicosanoid response appears to be restricted to specific conditions which depend on cell type, stimulus or lipid mediator to be formed [58,, , , , , , , , ]. In some of the latter studies, a certain preference of iPLA2-VIA for cleaving AA-containing ether phospholipids was noted [105,106]. More recent work has demonstrated that iPLA2-VIA participates in fatty adenosine kinase remodeling reactions aimed at removing oxidized fatty acyl chains within cardiolipin molecular species . This process, which can be regarded as a special case of the originally described phospholipid remodeling function of iPLA2-VIA, and also agrees with previous observations that oxidation of membranes accelerates iPLA2VIA-catalyzed fatty acid release [28,108], yields monolysocardiolipins that can be esterified back by new non-oxidized fatty acid. The reparation of oxidized phospholipids confers protection of β-cells against external injury . It is interesting to note in this regard that the closely related enzyme iPLA2-VIB (iPLA2γ) has also been shown to play a major role in mediating the release of oxidized acyl chains from oxidized cardiolipins, leading to the production of second messengers and the removal of toxic products derived from oxidative stress in mouse myocardium . A major open question in the field of lipid mediators is the molecular nature of the PLA2 enzyme involved in the release of DHA and related omega-3 fatty acids from phospholipids as a first committed step for the generation of SPMs. Although by analogy with AA it is often assumed that cPLA2α may serve this role, currently there is no direct evidence for this and, as discussed in the previous section, the in vitro specificity data are not revealing in this regard. Importantly, several recent studies provide evidence to suggest that iPLA2-VIA may fulfill this role in brain. DHA is found at high concentrations in the sn-2 position of brain membrane phospholipids and is critical for maintaining normal brain structure, function and metabolism, participating in signal transduction, gene transcription, and membrane stability . It has been shown that Pla2g6−/− mice exhibit disturbances in brain lipid composition and metabolism, which are associated with reduced incorporation of unesterified DHA from plasma into brain lipids and reduced esterified DHA concentrations in lipid classes [, , ]. Because DHA is the precursor of anti-inflammatory SPMs, the reduced brain DHA metabolism in the Pla2g6−/− mice may increase their vulnerability to neuroinflammation [, , , ]. An unexpected result regarding the substrate selectivity of iPLA2-VIA in cells has come from studies in mouse peritoneal macrophages . Using pharmacological approaches and lipidomic strategies, evidence was obtained that cPLA2α and iPLA2-VIA act on different phospholipid pools. While the former regulates AA release and eicosanoid production, the later acts on phospholipids that do not contain AA. iPLA2-VIA appears to selectively hydrolyze choline glycerophospholipids with palmitic acid at the sn-1 position, resulting in the production of palmitate-containing lysoPC, a lysophospholipid species with defined biological roles [85,118] (Fig. 3). Thus, iPLA2-VIA also takes part in signaling cascades leading to the generation of lipid mediators. Interestingly, this selectivity of iPLA2-VIA for PC containing palmitic acid at the sn-1 position had also been appreciated in a prior study utilizing iPLA2-VIA-overexpressing HEK293 cells . These two studies suggest more selectivity at the cellular level than observed for the in vitro selectivity of the pure recombinant human iPLA2-VIA for the sn-1 fatty acid or phospholipid headgroup , pointing out the intriguing possibility that, in a physiological environment, iPLA2-VIA could be compartmentalized in specific membranes enriched in palmitic acid-containing lipids.