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

Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

¹Correspondence: Center for Experimental Therapeutics and Reperfusion Injury, Thorn Building for Medical Research, 7th Floor, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115, USA. E-mail: cnserhan{at}zeus.bwh.harvard.edu

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 TNF-induced NFB 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 (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 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 NFB. 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.—Devchand, P. R., Arita, M., Hong, S., Bannenberg, G., Moussignac, R.-L., Gronert, K., Serhan, C. N. Human ALX receptor regulates neutrophil recruitment in transgenic mice: roles in inflammation and host defense.

Key Words: eicosanoids • lipoxin A₄ • resolution of inflammation • inhibition of NFB • G-protein-coupled receptor

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