Cutting Edge: Lipoxins Rapidly Stimulate Nonphlogistic Phagocytosis of Apoptotic Neutrophils by Monocyte-Derived Macrophages

TLDR

Lipoxins are inflammation‑derived eicosanoids that inhibit neutrophil chemotaxis and adhesion, acting as braking signals to limit tissue injury. The study aimed to determine whether LXA4 enhances phagocytosis of apoptotic neutrophils by monocyte‑derived macrophages during inflammation resolution. LXA4 and stable synthetic analogues induced rapid, concentration‑dependent phagocytosis of apoptotic neutrophils without triggering IL‑8 or MCP‑1, an effect blocked by anti‑CD36, αvβ3, and CD18 antibodies, pertussis toxin, and 8‑bromo‑cAMP, and mimicked by Rp‑cAMP, while attenuating PGE2‑stimulated PKA activation, indicating LXA4 is an endogenous stimulus for neutrophil clearance and supporting use of synthetic analogues as anti‑inflammatory agents.

Abstract

Abstract Lipoxins (LX) are lipoxygenase-derived eicosanoids generated during inflammation. LX inhibit polymorphonuclear neutrophil (PMN) chemotaxis and adhesion and are putative braking signals for PMN-mediated tissue injury. In this study, we report that LXA4 promotes another important step in the resolution phase of inflammation, namely, phagocytosis of apoptotic PMN by monocyte-derived macrophages (Mφ). LXA4 triggered rapid, concentration-dependent uptake of apoptotic PMN. This bioactivity was shared by stable synthetic LXA4 analogues (picomolar concentrations) but not by other eicosanoids tested. LXA4-triggered phagocytosis did not provoke IL-8 or monocyte chemoattractant protein-1 release. LXA4-induced phagocytosis was attenuated by anti-CD36, αvβ3, and CD18 mAbs. LXA4-triggered PMN uptake was inhibited by pertussis toxin and by 8-bromo-cAMP and was mimicked by Rp-cAMP, a protein kinase A inhibitor. LXA4 attenuated PGE2-stimulated protein kinase A activation in Mφ. These results suggest that LXA4 is an endogenous stimulus for PMN clearance during inflammation and provide a novel rationale for using stable synthetic analogues as anti-inflammatory compounds in vivo.