TY - JOUR
T1 - Human ALX receptor regulates neutrophil recruitment in transgenic mice
T2 - Roles in inflammation and host defense
AU - Devchand, Pallavi R.
AU - Arita, Makoto
AU - Hong, Song
AU - Bannenberg, Gerard
AU - Moussignac, Rose Laure
AU - Gronert, Karsten
AU - Serhan, Charles N.
PY - 2003/4
Y1 - 2003/4
N2 - 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 (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 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.
AB - 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 (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 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.
KW - Eicosanoids
KW - G-protein-coupled receptor
KW - Inhibition of NFκB
KW - Lipoxin A
KW - Resolution of inflammation
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UR - http://www.scopus.com/inward/citedby.url?scp=0037387732&partnerID=8YFLogxK
U2 - 10.1096/fj.02-0770com
DO - 10.1096/fj.02-0770com
M3 - Article
C2 - 12665478
AN - SCOPUS:0037387732
SN - 0892-6638
VL - 17
SP - 652
EP - 659
JO - FASEB Journal
JF - FASEB Journal
IS - 6
ER -