title: Formyl-Peptide Receptor 2/3/Lipoxin A4 Receptor Regulates Neutrophil-Platelet Aggregation and Attenuates Cerebral Inflammation: Impact for Therapy in Cardiovascular Disease.
abstract: Platelet activation at sites of vascular injury is essential for hemostasis, but it is also a major pathomechanism underlying ischemic injury. Because anti-inflammatory therapies limit thrombosis and antithrombotic therapies reduce vascular inflammation, we tested the therapeutic potential of 2 proresolving endogenous mediators, annexin A1 N-terminal derived peptide (AnxA1Ac2-26) and aspirin-triggered lipoxin A4 (15-epi-lipoxin A4), on the cerebral microcirculation after ischemia/reperfusion injury. Furthermore, we tested whether the lipoxin A4 receptor formyl-peptide receptor 2/3 (Fpr2/3; ortholog to human FPR2/lipoxin A4 receptor) evoked neuroprotective functions after cerebral ischemia/reperfusion injury.
  
  
  
  Using intravital microscopy, we found that cerebral ischemia/reperfusion injury was accompanied by neutrophil and platelet activation and neutrophil-platelet aggregate formation within cerebral microvessels. Moreover, aspirin-triggered lipoxin A4 activation of neutrophil Fpr2/3 regulated neutrophil-platelet aggregate formation in the brain and inhibited the reactivity of the cerebral microvasculature. The same results were obtained with AnxA1Ac2-26 administration. Blocking Fpr2/lipoxin A4 receptor with the antagonist Boc2 reversed this effect, and treatments were ineffective in Fpr2/3 knockout mice, which displayed an exacerbated disease severity, evidenced by increased infarct area, blood-brain barrier dysfunction, increased neurological score, and elevated levels of cytokines. Furthermore, aspirin treatment significantly reduced cerebral leukocyte recruitment and increased endogenous levels of aspirin-triggered lipoxin A4, effects again mediated by Fpr2/3.
  
  
  
  Fpr2/lipoxin A4 receptor is a therapeutic target for initiating endogenous proresolving, anti-inflammatory pathways after cerebral ischemia/reperfusion injury.
authors.affiliation: From Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport (S.A.V., P.M.H., J.R., D.N.G., F.N.E.G.); Department for General and Visceral Surgery, University Hospital Muenster, Germany (F.B.); William Harvey Research Institute, Queen Mary University of London, UK (M.P.); and Division of Brain Sciences, Imperial College London, UK (F.N.E.G.).
authors.forename: Shantel A
authors.initials: SA
authors.lastname: Vital
authors.affiliation: From Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport (S.A.V., P.M.H., J.R., D.N.G., F.N.E.G.); Department for General and Visceral Surgery, University Hospital Muenster, Germany (F.B.); William Harvey Research Institute, Queen Mary University of London, UK (M.P.); and Division of Brain Sciences, Imperial College London, UK (F.N.E.G.).
authors.forename: Felix
authors.initials: F
authors.lastname: Becker
authors.affiliation: From Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport (S.A.V., P.M.H., J.R., D.N.G., F.N.E.G.); Department for General and Visceral Surgery, University Hospital Muenster, Germany (F.B.); William Harvey Research Institute, Queen Mary University of London, UK (M.P.); and Division of Brain Sciences, Imperial College London, UK (F.N.E.G.).
authors.forename: Paul M
authors.initials: PM
authors.lastname: Holloway
authors.affiliation: From Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport (S.A.V., P.M.H., J.R., D.N.G., F.N.E.G.); Department for General and Visceral Surgery, University Hospital Muenster, Germany (F.B.); William Harvey Research Institute, Queen Mary University of London, UK (M.P.); and Division of Brain Sciences, Imperial College London, UK (F.N.E.G.).
authors.forename: Janice
authors.initials: J
authors.lastname: Russell
authors.affiliation: From Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport (S.A.V., P.M.H., J.R., D.N.G., F.N.E.G.); Department for General and Visceral Surgery, University Hospital Muenster, Germany (F.B.); William Harvey Research Institute, Queen Mary University of London, UK (M.P.); and Division of Brain Sciences, Imperial College London, UK (F.N.E.G.).
authors.forename: Mauro
authors.initials: M
authors.lastname: Perretti
authors.affiliation: From Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport (S.A.V., P.M.H., J.R., D.N.G., F.N.E.G.); Department for General and Visceral Surgery, University Hospital Muenster, Germany (F.B.); William Harvey Research Institute, Queen Mary University of London, UK (M.P.); and Division of Brain Sciences, Imperial College London, UK (F.N.E.G.).
authors.forename: D Neil
authors.initials: DN
authors.lastname: Granger
authors.affiliation: From Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport (S.A.V., P.M.H., J.R., D.N.G., F.N.E.G.); Department for General and Visceral Surgery, University Hospital Muenster, Germany (F.B.); William Harvey Research Institute, Queen Mary University of London, UK (M.P.); and Division of Brain Sciences, Imperial College London, UK (F.N.E.G.). fgavin@lsuhsc.edu.
authors.forename: Felicity N E
authors.initials: FN
authors.lastname: Gavins
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017305:Annexin A1 / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000473:pathology / Q000628:therapy*; D002544:Cerebral Infarction / Q000473:pathology* / Q000517:prevention & control; D007249:Inflammation / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology*; D044042:Receptors, Formyl Peptide / Q000819:agonists / Q000502:physiology*
chemical_list: D017305:Annexin A1; C469985:FPR3 protein, human; C469988:Fpr1 protein, mouse; D044042:Receptors, Formyl Peptide; C481578:formyl peptide receptor 2, mouse
keywords: inflammation; ischemia reperfusion injury; stroke, ischemic