Human ALX receptor regulates neutrophil recruitment in transgenic mice: roles in inflammation and host defense

• Published in: The FASEB journal 2003-04, Vol.17 (6), p.652-659
• Main Authors: Devchand, Pallavi R., Arita, Makoto, Hong, Song, Bannenberg, Gerard, Moussignac, Rose‐Laure, Gronert, Karsten, Serhan, Charles N.
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Animals; Cell Line; Chromatography, Liquid - methods; Dinoprostone - pharmacology; eicosanoids; Female; G‐protein‐coupled receptor; Humans; Hydroxyeicosatetraenoic Acids - metabolism; Hydroxyeicosatetraenoic Acids - pharmacology; Inflammation - immunology; Inflammation - physiopathology; inhibition of NFκB; Leukotriene B4 - metabolism; Leukotriene B4 - pharmacology; lipoxin A4; lipoxin A4 receptors; Lipoxins; Male; Mass Spectrometry - methods; Mice; Mice, Transgenic; Neutrophil Infiltration - drug effects; Neutrophil Infiltration - immunology; NF-kappa B - drug effects; NF-kappa B - metabolism; Peritoneum - drug effects; Peritoneum - metabolism; Peritoneum - pathology; Peritonitis - chemically induced; Peritonitis - genetics; Peritonitis - therapy; Plasmids - genetics; Receptors, Cell Surface - genetics; Receptors, Cell Surface - physiology; Receptors, Formyl Peptide; Receptors, Lipoxin; resolution of inflammation; Skin - drug effects; Skin - immunology; Skin - pathology; Transfection; Tumor Necrosis Factor-alpha - pharmacology; Zymosan
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.02-0770com

ABSTRACT Signaling pathways instrumental in the temporal and spatial progression of acute inflammation toward resolution are of wide interest. Here a transgenic mouse with myeloid‐selective expression of human lipoxin A4 receptor (hALX) was prepared and used to evaluate in vivo the effect of hALX expression. hALX‐transfected HEK293 cells transmitted LXA4 signals that inhibit TNFα‐induced NFκB activation. Transgenic FvB mice were generated by DNA injections of a 3.8 kb transgene consisting of the full‐length hALX cDNA driven by a fragment of the hCD11b promoter. When topically challenged via dermal ear skin, hALX transgenic mice gave attenuated neutrophil infiltration (∼80% reduction) in response to leukotriene B4 (LTB4) plus prostaglandin E2 (PGE2) as well as ∼50% reduction in PMN infiltrates (P50% reduction in PMN infiltrates to suboptimal doses (10 ng/mouse) of the ligand lipoxin A4 stable analog compared with < 10% reduction of PMN in nontransgenic littermates. Soluble mediators generated within the local inflammatory milieu of hALX mice showed diminished ability to activate the proinflammatory transcription factor NFκB. Analyses of the lipid‐derived mediators from exudates using LC‐MS tandem mass spectroscopy indicated an altered profile in hALX transgenic mice that included lower levels of LTB4 and increased amounts of lipoxin A4 compared with nontransgenic littermates. Together these results demonstrate a gain‐of‐function with hALX transgenic mouse and indicate that ALX is a key receptor and sensor in formation of acute exudates and their resolution.