Activation of Lipoxin a4 Receptors by Aspirin-Triggered Lipoxins and Select Peptides Evokes Ligand-Specific Responses in Inflammation

N Chiang, IM Fierro, K Gronert… - The Journal of …, 2000 - rupress.org
The Journal of experimental medicine, 2000rupress.org
Lipoxin (LX) A4 and aspirin-triggered LX (ATL) are endogenous lipids that regulate
leukocyte trafficking via specific LXA4 receptors (ALXRs) and mediate antiinflammation and
resolution. ATL analogues dramatically inhibited human neutrophil (polymorphonuclear
leukocyte [PMN]) responses evoked by a potent necrotactic peptide derived from
mitochondria as well as a rogue synthetic chemotactic peptide. These bioactive lipid
analogues and small peptides each selectively competed for specific 3H-LXA4 binding with …
Lipoxin (LX) A4 and aspirin-triggered LX (ATL) are endogenous lipids that regulate leukocyte trafficking via specific LXA4 receptors (ALXRs) and mediate antiinflammation and resolution. ATL analogues dramatically inhibited human neutrophil (polymorphonuclear leukocyte [PMN]) responses evoked by a potent necrotactic peptide derived from mitochondria as well as a rogue synthetic chemotactic peptide. These bioactive lipid analogues and small peptides each selectively competed for specific 3H-LXA4 binding with recombinant human ALXR, and its N-glycosylation proved essential for peptide but not LXA4 recognition. Chimeric receptors constructed from receptors with opposing functions, namely ALXR and leukotriene B4 receptors (BLTs), revealed that the seventh transmembrane segment and adjacent regions of ALXR are essential for LXA4 recognition, and additional regions of ALXR are required for high affinity binding of the peptide ligands. Together, these findings are the first to indicate that a single seven-transmembrane receptor can switch recognition as well as function with certain chemotactic peptides to inhibitory with ATL and LX (lipid ligands). Moreover, they suggest that ALXR activation by LX or ATL can protect the host from potentially deleterious PMN responses associated with innate immunity as well as direct effector responses in tissue injury by recognition of peptide fragments.
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