Leukocyte antiadhesive actions of annexin 1: ALXR- and FPR-related anti-inflammatory mechanisms.
Recent investigations conducted with human neutrophils have indicated an involvement for the receptor for formylated peptides, termed FPR, and its analog FPRL1 (or ALXR because it is the receptor for the endogenous ligand lipoxin A(4)) in the in vitro inhibitory actions of the glucocorticoid-regulated protein annexin 1 and its peptidomimetics. To translate these findings in in vivo settings, we have used an ischemia/reperfusion (I/R) procedure to promote leukocyte-endothelium interactions in the mouse mesenteric microcirculation. In naive mice, the annexin 1 mimetic peptide Ac2-26 (20 to 100 microg administered intravenously prior to reperfusion) abolished I/R-induced cell adhesion and emigration, but not cell rolling. In FPR-deficient mice, peptide Ac2-26 retained significant inhibitory actions (about 50% of the effects in naive mice), and these were blocked by an FPR antagonist, termed butyloxycarbonyl-Phe-Leu-Phe-Leu-Phe, or Boc2. In vitro, neutrophils taken from these animals could be activated at high concentrations of formyl-Met-Leu-Phe (30 microM; fMLP), and this effect was blocked by cell incubation with peptide Ac2-26 (66 microM) or Boc2 (100 microM). FPR-deficient neutrophils expressed ALXR mRNA and protein. Both ALXR agonists, lipoxin A(4) and peptide Ac2-26, provoked detachment of adherent leukocytes in naive as well as in FPR-deficient mice, whereas the CXC chemokine KC or fMLP were inactive. The present findings demonstrate that endogenous regulatory autocoids such as lipoxin A(4) and annexin 1-derived peptides function to disengage adherent cells during cell-cell interactions.
Gavins
Felicity N E
FN
William Harvey Research Institute, Bart's and the Royal London, Queen Mary School of Medicine and Dentistry, Charterhouse Square, London, United Kingdom.
Yona
Simon
S
Kamal
Ahmad M
AM
Flower
Roderick J
RJ
Perretti
Mauro
M
D000818:Animals; D017305:Annexin A1 / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology*; D003433:Crosses, Genetic; D006801:Humans; D007249:Inflammation / Q000503:physiopathology* / Q000517:prevention & control; D007962:Leukocytes / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D044067:Receptors, Lipoxin; D018000:Receptors, Peptide / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D017305:Annexin A1; C105101:FPR2 protein, human; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic; D044067:Receptors, Lipoxin; D018000:Receptors, Peptide