Pla2g5 contributes to viral‐like‐induced lung inflammation through macrophage proliferation and LA/Ffar1 lung cell recruitment

Abstract

AbstractMacrophages expressing group V phospholipase A2 (Pla2g5) release the free fatty acid (FFA) linoleic acid (LA), potentiating lung type 2 inflammation. Although Pla2g5 and LA increase in viral infections, their role remains obscure. We generated Pla2g5flox/flox mice, deleted Pla2g5 by using the Cx3cr1cre transgene, and activated bone marrow‐derived macrophages (BM‐Macs) with poly:IC, a synthetic double‐stranded RNA that triggers a viral‐like immune response, known Pla2g5‐dependent stimuli (IL‐4, LPS + IFNγ, IL‐33 + IL‐4 + GM‐CSF) and poly:IC + LA followed by lipidomic and transcriptomic analysis. Poly:IC‐activated Pla2g5flox/flox;Cx3cr1cre/+ BM‐Macs had downregulation of major bioactive lipids and critical enzymes producing those bioactive lipids. In addition, AKT phosphorylation was lower in poly:IC‐stimulated Pla2g5flox/flox;Cx3cr1cre/+ BM‐Macs, which was not restored by adding LA to poly:IC‐stimulated BM‐Macs. Consistently, Pla2g5flox/flox;Cx3cr1cre/+ mice had diminished poly:IC‐induced lung inflammation, including inflammatory macrophage proliferation, while challenging Pla2g5flox/flox;Cx3cr1cre/+ mice with poly:IC + LA partially restored lung inflammation and inflammatory macrophage proliferation. Finally, mice lacking FFA receptor‐1 (Ffar1)‐null mice had reduced poly:IC‐induced lung cell recruitment and tissue macrophage proliferation, not corrected by LA. Thus, Pla2g5 contributes to poly:IC‐induced lung inflammation by regulating inflammatory macrophage proliferation and LA/Ffar1‐mediated lung cell recruitment and tissue macrophage proliferation.