Together, these data support the hypothesis that lyso-PS presented on the surface of activated and dying neutrophils provides a tightly controlled, proresolution signal for high capacity clearance of neutrophils in acute inflammation.Ī hallmark of acute inflammation is the recruitment of large numbers of neutrophils from the vasculature into tissues in response to microbial infection and/or injury. Further investigation revealed that the impact of this pathway, either the enhancement or inhibition of efferocytosis, was exquisitely sensitive to concentration effects of these intermediaries. These data were surprising in light of previous reports demonstrating that signaling by PGE 2 and adenylyl cyclase activation are associated with macrophage deactivation and inhibition of apoptotic cell uptake. These events, in turn, culminated in enhanced activity of Rac1, resulting in an increase in both the numbers of macrophages efferocytosing apoptotic cells and the numbers of cells ingested per macrophage. Subsequent signaling by PGE 2 via EP2 receptors activated macrophage adenylyl cyclase and protein kinase A. Lyso-PS, either made endogenously in apoptosing neutrophils or supplied exogenously in liposomes along with lyso-PS neg apoptotic cells, signaled to macrophages in a G2A-dependent manner for their enhanced production of prostaglandin E 2 (PGE 2) via a calcium-dependent cytosolic phospholipase A 2/cyclooxygenase-mediated mechanism. Here, we investigated the signaling pathway downstream of G2A. We have recently demonstrated that lysophosphatidylserine (lyso-PS) generated and retained on neutrophils following short term activation of the NADPH oxidase in vitro and in vivo enhanced their clearance via signaling through the macrophage G-protein-coupled receptor G2A. Phosphatidylserine (PS) and oxidized PS species have been identified as key ligands on apoptotic cells important for their recognition and removal (efferocytosis) by phagocytes, a requisite step for resolution of inflammation.
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