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Human ALX receptor regulates neutrophil recruitment in transgenic mice: roles in inflammation and host defense
Author(s) -
Devchand Pallavi R.,
Arita Makoto,
Hong Song,
Bannenberg Gerard,
Moussignac RoseLaure,
Gronert Karsten,
Serhan Charles N.
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0770com
Subject(s) - inflammation , transgene , receptor , genetically modified mouse , leukotriene b4 , proinflammatory cytokine , lipoxin , chemistry , endocrinology , biology , microbiology and biotechnology , immunology , medicine , biochemistry , gene
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 A 4 receptor (hALX) was prepared and used to evaluate in vivo the effect of hALX expression. hALX‐transfected HEK293 cells transmitted LXA 4 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 B 4 (LTB 4 ) plus prostaglandin E 2 (PGE 2 ) as well as ∼50% reduction in PMN infiltrates ( P <0.02) to receptor‐bypass inflammation evoked by phorbol ester. The hALX transgenic mice gave markedly decreased PMN infiltrates to the peritoneum with zymosan and altered the dynamics of this response. Transgenic hALX mice displayed increased sensitivity with >50% reduction in PMN infiltrates to suboptimal doses (10 ng/mouse) of the ligand lipoxin A 4 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 LTB 4 and increased amounts of lipoxin A 4 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.