Phospholipases A (PLAs) 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 (iPLAβ). Here, we assessed the link between iPLAβ-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 iPLAβ 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 PGFα, PGE, leukotriene B) and decreased ability to generate resolvin D2. These changes were not linked with secretory PLA or cytosolic PLAα or with leakage of the transgene. Thus, we report previously unidentified links between select iPLAβ-derived eicosanoids, an SPM, and macrophage polarization. Importantly, our findings reveal for the first time that β-cell iPLAβ-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.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997598PMC
http://dx.doi.org/10.1194/jlr.RA119000281DOI Listing

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