title: Lipoxins, aspirin-triggered epi-lipoxins, lipoxin stable analogues, and the resolution of inflammation: stimulation of macrophage phagocytosis of apoptotic neutrophils in vivo.
abstract: Lipoxins (LX) are eicosanoids with antiinflammatory activity in glomerulonephritis (GN) and inflammatory diseases, hypersensitivity, and ischemia reperfusion injury. It has been demonstrated that LXA(4) stimulates non-phlogistic phagocytosis of apoptotic polymorphonuclear neutrophils (PMN) by monocyte-derived macrophages (Mphi) in vitro, suggesting a role for LX as endogenous pro-resolution lipid mediators. It is here reported that LXA(4), LXB(4), the aspirin-triggered LX (ATL) epimer, 15-epi-LXB(4), and a stable synthetic analogue 15(R/S)-methyl-LXA(4) stimulate phagocytosis of exogenously administered excess apoptotic PMN by macrophages (M phi) 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 LXA(4), LXB(4), 15(R/S)-methyl-LXA(4), and 15-epi-LXB(4) of 2.5 to 10 micro g/kg. Non-phlogistic LX-stimulated phagocytosis by M phi was sensitive to inhibition of PKC and PI 3-kinase and associated with increased production of transforming growth factor-beta(1) (TGF-beta(1)). LX-stimulated phagocytosis was not inhibited by phosphatidylserine receptor (PSR) antisera and was abolished by prior exposure of M phi to beta 1,3-glucan, suggesting a novel M phi-PMN recognition mechanism. Interestingly, the recently described peptide agonists of the LXA(4) receptor (MYFINITL and LESIFRSLLFRVM) stimulated phagocytosis through a process associated with increased TGF-beta(1) release. These data provide the first demonstration that LXA(4), LXB(4), ATL, and LX stable analogues rapidly promote M phi 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.
authors.affiliation: Centre for Molecular Inflammation and Vascular Research, Mater Misericordiae Hospital and Department of Medicine and Therapeutics, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Ireland.
authors.forename: Siobhan
authors.initials: S
authors.lastname: Mitchell
authors.forename: Graham
authors.initials: G
authors.lastname: Thomas
authors.forename: Killeen
authors.initials: K
authors.lastname: Harvey
authors.forename: David
authors.initials: D
authors.lastname: Cottell
authors.forename: Keira
authors.initials: K
authors.lastname: Reville
authors.forename: Giovanni
authors.initials: G
authors.lastname: Berlasconi
authors.forename: Nicos A
authors.initials: NA
authors.lastname: Petasis
authors.forename: Lars
authors.initials: L
authors.lastname: Erwig
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Rees
authors.forename: John
authors.initials: J
authors.lastname: Savill
authors.forename: Hugh R
authors.initials: HR
authors.lastname: Brady
authors.forename: Catherine
authors.initials: C
authors.lastname: Godson
mesh_terms: D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D001241:Aspirin / Q000494:pharmacology; D001853:Bone Marrow / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004355:Drug Stability; D015777:Eicosanoids / Q000737:chemistry / Q000378:metabolism*; D004798:Enzymes / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D056484:Jumonji Domain-Containing Histone Demethylases; D008055:Lipids / Q000494:pharmacology; D008264:Macrophages / Q000502:physiology*; D009504:Neutrophils / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology*; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000819:agonists / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D015777:Eicosanoids; D004798:Enzymes; D008055:Lipids; D010455:Peptides; D011956:Receptors, Cell Surface; C408123:phosphatidylserine receptor; D000242:Cyclic AMP; C498707:JMJD6 protein, human; D056484:Jumonji Domain-Containing Histone Demethylases; D001241:Aspirin