Resolvin E1 modulates Mac-1 signaling and promotes neutrophil apoptosis and the resolution of acute inflammation (P5064)

Abstract

Abstract Resolvin E1 (RvE1), derived from the omega-3 polyunsaturated fatty acid eicosapentaenoic acid inhibits Mac-1 (CD11b/CD18)-mediated neutrophil trafficking. Mac-1also generates ligand-specific outside-in signals to modulate neutrophil apoptosis, a critical control point in the resolution of inflammation. We studied the impact of RvE1 on Mac-1signaling and neutrophil apoptosis. Culture of human neutrophils with RvE1 (0.1-10 nM) mitigated ERK and Akt-mediated survival signals from the Mac-1 ligand myeloperoxidase, leading to Mcl-1 degradation and mitochondrial dysfunction. RvE1 facilitated phagocytosis of C3b-opsonized E. coli and triggered phagocytosis-induced apoptosis. RvE1 through the leukotriene B4 receptor BLT1 evoked ROS generation by NADPH oxidase, leading to activation of caspase-8 and 3. In mice, treatment with RvE1 at the peak of inflammation enhanced the resolution of E. coli pneumonia, E. coli peritonitis-associated and carrageenan plus myeloperoxidase-evoked neutrophil-mediated lung injury through facilitating neutrophil apoptosis and removal of apoptotic neutrophils by macrophages. These actions of RvE1 were prevented by the pan-caspase inhibitor zVAD-fmk. Our results identify a novel resolution circuit, in which RvE1 through BLT1 shifts the balance between Mac-1-generated competing pro- and anti-apoptotic signals toward apoptotic pathways, and consequently enhances resolution of acute lung inflammation.