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 ␤) causes accumulation of arachidonic acid, lysophospholipids, and eicosanoids that can promote inflammation and pathologic states.We examined the role of iPLA 2 ␤ in peritoneal macrophage immune function by comparing wild type (WT) and iPLA 2 ␤ ؊/؊ mouse macrophages.Compared with WT, iPLA 2 ␤ ؊/؊ macrophages exhibited reduced proinflammatory M1 markers when classically activated.In contrast, antiinflammatory M2 markers were elevated under naïve conditions and induced to higher levels by alternative activation in iPLA 2 ␤ ؊/؊ 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 ␤ ؊/؊ macrophages compared with WT.The effects of inhibitors of iPLA 2 ␤, 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 ␤ ؊/؊ macrophages, but none tested promoted M2 phenotype.These findings suggest that (a) lipids generated by iPLA 2 ␤ and subsequently oxidized by cyclooxygenase and 12-LO favor macrophage inflammatory M1 polarization, and (b) the absence of iPLA 2 ␤ promotes macrophage M2 polarization.Reducing macrophage iPLA 2 ␤ activity and thereby attenuating macrophage M1 polarization might cause a shift from an inflammatory to a recovery/repair milieu.Macrophages are important in inflammation.These mononuclear myeloid hematopoietic lineage cells contribute to both innate and adaptive immunity (1).In the innate immune response, macrophages phagocytose invading pathogens and modulate recruitment and activation of inflammatory cells with secreted factors such as tumor necrosis factor ␣ (TNF␣) and prostaglandin E 2 (PGE 2 ) 3 (2, 3).Macrophages facilitate adaptive immunity primarily as antigen-presenting cells (4).Phagocytosed proteins processed into small fragments can be presented to CD4 ϩ T cells via the major histocompatibility class II receptor (MHC II) (5).The critical role of macrophages in initiation and resolution of infection can be observed in models of macrophage depletion; in cases of macrophage insufficiency, experimental mice have an increased susceptibility to infection, and existing infections progress further than in macrophage-sufficient animals (6).Macrophages also contribute to the pathogenesis of cancer progression, rheumatoid arthritis, diabetes, and atherosclerosis; macrophages are thus targets of emerging therapeutic regimens (7-10).Macrophages also participate in autoimmune-mediated destruction of ␤-cells and type 1 diabetes (T1D).In diabetesprone individuals, immune cells including macrophages migrate to pancreatic islets and secrete proinflammatory cyto-* This work was supported, in whole or in part, by NIDDK, National Institutes of Health