Activation of lipoxin A(4) receptors by aspirin-triggered lipoxins and select peptides evokes ligand-specific responses in inflammation

J Exp Med. 2000 Apr 3;191(7):1197-208. doi: 10.1084/jem.191.7.1197.

Abstract

Lipoxin (LX) A(4) and aspirin-triggered LX (ATL) are endogenous lipids that regulate leukocyte trafficking via specific LXA(4) 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 (3)H-LXA(4) binding with recombinant human ALXR, and its N-glycosylation proved essential for peptide but not LXA(4) recognition. Chimeric receptors constructed from receptors with opposing functions, namely ALXR and leukotriene B(4) receptors (BLTs), revealed that the seventh transmembrane segment and adjacent regions of ALXR are essential for LXA(4) 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / immunology*
  • Aspirin
  • CHO Cells
  • Calcium / metabolism
  • Cell Line
  • Chemokine CCL4
  • Chemokine CXCL2
  • Cricetinae
  • Humans
  • Hydroxyeicosatetraenoic Acids / immunology*
  • Ligands
  • Lipoxins*
  • Macrophage Inflammatory Proteins / genetics
  • Macrophage Inflammatory Proteins / metabolism
  • Major Histocompatibility Complex / immunology*
  • Molecular Structure
  • Monokines / genetics
  • Monokines / metabolism
  • Neutrophils / drug effects
  • Neutrophils / immunology
  • Oligopeptides / chemistry
  • Oligopeptides / immunology*
  • Peptides / chemistry
  • Peptides / immunology*
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / immunology*
  • Receptors, Formyl Peptide*
  • Receptors, Leukotriene B4 / genetics
  • Receptors, Leukotriene B4 / immunology
  • Receptors, Lipoxin*
  • Serum Amyloid A Protein / metabolism
  • Signal Transduction

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Chemokine CCL4
  • Chemokine CXCL2
  • FPR2 protein, human
  • Hydroxyeicosatetraenoic Acids
  • Ligands
  • Lipoxins
  • MHC binding peptide
  • MMK-1 peptide
  • Macrophage Inflammatory Proteins
  • Monokines
  • Oligopeptides
  • Peptides
  • Receptors, Cell Surface
  • Receptors, Formyl Peptide
  • Receptors, Leukotriene B4
  • Receptors, Lipoxin
  • Serum Amyloid A Protein
  • lipoxin A4
  • Aspirin
  • Calcium