Lipoxins, Aspirin-Triggered Epi-Lipoxins, Lipoxin Stable Analogues, and the Resolution of Inflammation: Stimulation of Macrophage Phagocytosis of Apoptotic Neutrophils In Vivo

Abstract

ABSTRACT. Lipoxins (LX) are eicosanoids with antiinflammatory activity in glomerulonephritis (GN) and inflammatory diseases, hypersensitivity, and ischemia reperfusion injury. It has been demonstrated that LXA4 stimulates non-phlogistic phagocytosis of apoptotic polymorphonuclear neutrophils (PMN) by monocyte-derived macrophages (Mφ) in vitro, suggesting a role for LX as endogenous pro-resolution lipid mediators. It is here reported that LXA4, LXB4, the aspirin-triggered LX (ATL) epimer, 15-epi-LXB4, and a stable synthetic analogue 15(R/S)-methyl-LXA4 stimulate phagocytosis of exogenously administered excess apoptotic PMN by macrophages (Mφ) in vivo in a classic model of acute inflammation, namely thioglycollate-induced peritonitis. Significant enhancement of phagocytosis in vivo was observed with 15-min exposure to LX and with intraperitoneal doses of LXA4, LXB4, 15(R/S)-methyl-LXA4, and 15-epi-LXB4 of 2.5 to 10 μg/kg. Non-phlogistic LX-stimulated phagocytosis by Mφ was sensitive to inhibition of PKC and PI 3-kinase and associated with increased production of transforming growth factor–β1 (TGF-β1). LX-stimulated phagocytosis was not inhibited by phosphatidylserine receptor (PSR) antisera and was abolished by prior exposure of Mφ to β1,3-glucan, suggesting a novel Mφ-PMN recognition mechanism. Interestingly, the recently described peptide agonists of the LXA4 receptor (MYFINITL and LESIFRSLLFRVM) stimulated phagocytosis through a process associated with increased TGF-β1 release. These data provide the first demonstration that LXA4, LXB4, ATL, and LX stable analogues rapidly promote Mφ phagocytosis of PMN in vivo and support a role for LX as rapidly acting, pro-resolution signals in inflammation. Engagement of the LXR by LX generated during cell-cell interactions in inflammation and by endogenous LXR peptide agonists released from distressed cells may be an important stimulus for clearance of apoptotic cells and may be amenable to pharmacologic mimicry for therapeutic gain.E-mail: cgodson@mater.ie