Abstract
Phospholipases A(2) (PLA(2)s) catalyze hydrolysis of the sn-2 substituent from glycerophospholipids to yield a free fatty acid (i.e., arachidonic acid), which can be metabolized to pro- or anti-inflammatory eicosanoids. Macrophages modulate inflammatory responses and are affected by Ca2+-independent phospholipase A(2) (PLA(2))beta (iPLA(2)beta). Here, we assessed the link between iPLA(2)beta-derived lipids (iDLs) and macrophage polarization. Macrophages from WT and KO (iPLA(2)beta-/-) mice were classically M1 pro-inflammatory phenotype activated or alternatively M2 anti-inflammatory phenotype activated, and eicosanoid production was determined by ultra-performance LC ESI-MS/MS. As a genotypic control, we performed similar analyses on macrophages from RIP.iPLA(2)beta.Tg mice with selective iPLA(2)beta overexpression in beta-cells. Compared with WT, generation of select pro-inflammatory prostaglandins (PGs) was lower in iPLA(2)beta(-/-), and that of a specialized pro-resolving lipid mediator (SPM), resolvin D2, was higher; both changes are consistent with the M2 phenotype. Conversely, macrophages from RIP.iPLA(2)beta.Tg mice exhibited an opposite landscape, one associated with the M1 phenotype: namely, increased production of pro-inflammatory eicosanoids (6-keto PGF(1)alpha, PGE(2), leukotriene B-4) and decreased ability to generate resolvin D2. These changes were not linked with secretory PLA(2) or cytosolic PLA(2)alpha or with leakage of the transgene. Thus, we report previously unidentified links between select iPLA(2)beta-derived eicosanoids, an SPM, and macrophage polarization. Importantly, our findings reveal for the first time that beta-cell iPLA(2)beta-derived signaling can predispose macrophage responses. These findings suggest that iDLs play critical roles in macrophage polarization, and we posit that they could be targeted therapeutically to counter inflammation-based disorders.