Macrophage polarization is linked to Ca 2+ -independent phospholipase A 2 β-derived lipids and cross-cell signaling in mice

Phospholipases A (PLA s) catalyze hydrolysis of the -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 Ca -independent phospholipase A (PLA )β (iPLA β). Here, we assessed the link between iPLA β-derived lipids (iDLs) and macrophage polarization. Macrophages from WT and KO ( ) 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 mice with selective iPLA β overexpression in β-cells. Compared with WT, generation of select pro-inflammatory prostaglandins (PGs) was lower in , 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 mice exhibited an opposite landscape, one associated with the M1 phenotype: namely, increased production of pro-inflammatory eicosanoids (6-keto PGF α, PGE , leukotriene B ) and decreased ability to generate resolvin D2. These changes were not linked with secretory PLA or cytosolic PLA α or with leakage of the transgene. Thus, we report previously unidentified links between select iPLA β-derived eicosanoids, an SPM, and macrophage polarization. Importantly, our findings reveal for the first time that β-cell iPLA β-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.