Polarization of Macrophages toward M2 Phenotype Is Favored by Reduction in iPLA2β (Group VIA Phospholipase A2)

Macrophages are important in innate and adaptive immunity. Macrophage participation in inflammation or tissue repair is directed by various extracellular signals and mediated by multiple intracellular pathways. Activation of group VIA phospholipase A(2) (iPLA(2)beta) causes accumulation of arachidonic acid, lysophospholipids, and eicosanoids that can promote inflammation and pathologic states. We examined the role of iPLA(2)beta in peritoneal macrophage immune function by comparing wild type (WT) and iPLA(2)beta(-/-) mouse macrophages. Compared with WT, iPLA(2)beta(-/-) macrophages exhibited reduced proinflammatory M1 markers when classically activated. In contrast, antiinflammatory M2 markers were elevated under naive conditions and induced to higher levels by alternative activation in iPLA(2)beta(-/-) macrophages compared with WT. Induction of eicosanoid (12-lipoxygenase (12-LO) and cyclooxygenase 2 (COX2))-and reactive oxygen species (NADPH oxidase 4 (NOX4))-generating enzymes by classical activation pathways was also blunted in iPLA(2)beta(-/-) macrophages compared with WT. The effects of inhibitors of iPLA(2)beta, COX2, or 12-LO to reduce M1 polarization were greater than those to enhance M2 polarization. Certain lipids (lysophosphatidylcholine, lysophosphatidic acid, and prostaglandin E-2) recapitulated M1 phenotype in iPLA(2)beta(-/-) macrophages, but none tested promoted M2 phenotype. These findings suggest that (a) lipids generated by iPLA(2)beta and subsequently oxidized by cyclooxygenase and 12-LO favor macrophage inflammatory M1 polarization, and (b) the absence of iPLA(2)beta promotes macrophage M2 polarization. Reducing macrophage iPLA(2)beta activity and thereby attenuating macrophage M1 polarization might cause a shift from an inflammatory to a recovery/repair milieu.