title: Targeting formyl peptide receptor 2 reduces leukocyte-endothelial interactions in a murine model of stroke.
abstract: Ischemia/reperfusion (I/R) injury following stroke can worsen patient outcome through excess inflammation. This study investigated the pharmacologic potential of targeting an endogenous anti-inflammatory circuit via formyl peptide receptor (FPR) 2/lipoxin receptor (ALX) (Fpr2/3 in mouse) in global cerebral I/R. Mice (C57BL/6 and Fpr2/3(-/-)) were subjected to bilateral common carotid artery occlusion, followed by reperfusion and treatment with FPR agonists: AnxA1Ac2-26 [Annexin A1 mimetic peptide (Ac-AMVSEFLKQAWFIENEEQEYVQTVK), 2.5 μg/kg] and 15-epimer-lipoxin A4 (15-epi-LXA4; FPR2/ALX specific, 12.5 and 100 ng/kg). Leukocyte-endothelial (L-E) interactions in the cerebral microvasculature were then quantified in vivo using intravital fluorescence microscopy. 15-epi-LXA4 administration at the start of reperfusion reduced L-E interactions after 40 min (which was sustained at 2 h with high-dose 15-epi-LXA4) to levels seen in sham-operated animals. AnxA1Ac2-26 treatment decreased leukocyte adhesion at 40 min and all L-E interactions at 2 h (up to 95%). Combined treatment with AnxA1Ac2-26 plus FPR antagonists t-Boc-FLFLF (250 ng/kg) or WRW4 (FPR2/ALX selective, 1.4 μg/kg) abrogated the effects of AnxA1Ac2-26 fully at 40 min. Antagonists were less effective at 2 h, which we demonstrate is likely because of their impact on early L-E interactions. Our findings indicate that FPR2/ALX activity elicits considerable control over vascular inflammatory responses during cerebral I/R and, therefore, provide evidence that targeting FPR2/ALX may be beneficial for patients who suffered from stroke.
authors.affiliation: *Molecular and Cellular Physiology Department, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA; Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom; and Departments of Morphology and Genetics and Biology, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Helen K
authors.initials: HK
authors.lastname: Smith
authors.affiliation: *Molecular and Cellular Physiology Department, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA; Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom; and Departments of Morphology and Genetics and Biology, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Cristiane Damas
authors.initials: CD
authors.lastname: Gil
authors.affiliation: *Molecular and Cellular Physiology Department, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA; Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom; and Departments of Morphology and Genetics and Biology, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Oliani
authors.affiliation: *Molecular and Cellular Physiology Department, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA; Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom; and Departments of Morphology and Genetics and Biology, Federal University of São Paulo, São Paulo, Brazil f.gavins@imperial.ac.uk.
authors.forename: Felicity N E
authors.initials: FN
authors.lastname: Gavins
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D017305:Annexin A1 / Q000378:metabolism; D015153:Blotting, Western; D002340:Carotid Artery Diseases / Q000473:pathology / Q000517:prevention & control; D002448:Cell Adhesion; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000473:pathology / Q000517:prevention & control; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D055806:Microvessels / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D044042:Receptors, Formyl Peptide / Q000502:physiology*; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control; D020521:Stroke / Q000503:physiopathology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017305:Annexin A1; C509871:HSH2 protein, mouse; D010446:Peptide Fragments; D044042:Receptors, Formyl Peptide; C573274:annexin A1, mouse; C481578:formyl peptide receptor 2, mouse
keywords: Annexin A1; FPR2/ALX; inflammation; ischemia/reperfusion