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

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.

The Melanocortin Agonist AP214 Exerts Anti-Inflammatory and Proresolving Properties

“…42,43 Furthermore, recognition of apoptotic neutrophils exerts additional anti-inflammatory effects because it leads back to inhibit the release of pro-inflammatory mediators and activate the production of anti-inflammatory IL-10 and TGF-␤. 44 -46 Many proinflammatory mediators, such as annexin A1, glucocorticoid, and lipoxin A 4 , have been shown to produce proefferocytic effects, [47][48][49] but no data are available with respect to MC receptor agonists. Using plate-based and validated in vivo protocols, 23,24 we observed that AP214 evoked a marked increase in the phagocytosis of human apoptotic neutrophils by cultured macrophages in vitro (with an increment of ϳ70%) and resident peritoneal macrophages in vivo (30%).…”

Microglia and Monocyte-Derived Macrophages in Stroke

“…Four distinct chemical families have been identified and named lipoxins, resolvins, protectins, and maresins. These families are biosynthesized in acute inflammation and control the duration and magnitude of inflammation via activation of mononuclear phagocyte recruitment, uptake of apoptotic neutrophils by the phagocytes, endogenous antimicrobial defense mechanisms, and clearance on mucosal surfaces [132][133][134][135][136][137][138]. An additional modulator for tissue repair and remodeling in the CNS injury is arginase-1.…”

Aspirin-Triggered Lipoxins Override the Apoptosis-Delaying Action of Serum Amyloid A in Human Neutrophils: A Novel Mechanism for Resolution of Inflammation

“…To assess the functional receptor that mediates the apoptosis suppressing action of SAA, we used Boc2 (27). Preincubation of PMN with Boc2 attenuated the effects of SAA on PMN viability and annexin V staining by 80 -97% (Fig.…”

“…22) and suppress IL-8 secretion (25). Annexin-1 accelerates PMN apoptosis (26), whereas LXA 4 /15-epi-LXA 4 does not affect PMN apoptosis (25,27). Thus, activation of ALX may result in potent proinflammatory or anti-inflammatory responses in a ligand-specific fashion.…”