title: Proresolving and tissue-protective actions of annexin A1-based cleavage-resistant peptides are mediated by formyl peptide receptor 2/lipoxin A4 receptor.
abstract: Endogenous mechanisms regulating the host response during inflammation resolution are critical in ensuring disposal of noxious stimuli and return to homeostasis. In this article, we engineered novel Annexin A1 (AnxA1)-based peptides, AnxA1(2-50), that displayed specific binding to the AnxA1 receptor (formyl peptide receptor 2/Lipoxin A4 receptor [FPR2/ALX]; IC50 ∼4 nM). Intravenous administration of AnxA1(2-50) markedly reduced (>60%) leukocyte adhesion to postcapillary venules in wild type and Fpr1(-/-), but not Fpr2/Alx(-/-), mice. Generation of a metabolically stable form of this peptide (CR-AnxA1(2-50)), engineered by substituting a cleavage site shared by human proteinase 3 and neutrophil elastase, yielded an agonist that was resistant to neutrophil-mediated cleavage and displayed enhanced proresolving actions: accelerated resolution of self-limited inflammation and enhanced macrophage efferocytosis after sterile injury, when compared with AnxA1(2-50). These actions were retained with human primary leukocytes where CR-AnxA1(2-50) decreased neutrophil-endothelial interactions (∼25-45%), and stimulated neutrophil apoptosis and macrophage efferocytosis (∼45%). In murine cardiac ischemia/reperfusion injury, CR-AnxA1(2-50) elicited tissue-protective actions reducing infarct size (∼60%) and incidence of 24-h death. These results identify AnxA1(2-50) and CR-AnxA1(2-50) as FPR2/ALX agonists that harness the proresolving actions of AnxA1, and thus may represent therapeutic tools for treatment of inflammatory conditions.
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
authors.forename: Jesmond
authors.initials: J
authors.lastname: Dalli
authors.forename: Angelo P
authors.initials: AP
authors.lastname: Consalvo
authors.forename: Vicki
authors.initials: V
authors.lastname: Ray
authors.forename: Clara
authors.initials: C
authors.lastname: Di Filippo
authors.forename: Michele
authors.initials: M
authors.lastname: D'Amico
authors.forename: Nozer
authors.initials: N
authors.lastname: Mehta
authors.forename: Mauro
authors.initials: M
authors.lastname: Perretti
mesh_terms: D000818:Animals; D017305:Annexin A1 / Q000276:immunology* / Q000378:metabolism; D000893:Anti-Inflammatory Agents / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism; D010455:Peptides / Q000276:immunology; D010587:Phagocytosis / Q000276:immunology; D044042:Receptors, Formyl Peptide / Q000819:agonists* / Q000276:immunology*; D044067:Receptors, Lipoxin / Q000819:agonists* / Q000276:immunology*
chemical_list: D017305:Annexin A1; D000893:Anti-Inflammatory Agents; C105101:FPR2 protein, human; D010455:Peptides; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin