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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.
AuthorsJesmond Dalli, Angelo P Consalvo, Vicki Ray, Clara Di Filippo, Michele D'Amico, Nozer Mehta, Mauro Perretti
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 190 Issue 12 Pg. 6478-87 (Jun 15 2013) ISSN: 1550-6606 [Electronic] United States
PMID23686496 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Annexin A1
  • Anti-Inflammatory Agents
  • FPR2 protein, human
  • Peptides
  • Receptors, Formyl Peptide
  • Receptors, Lipoxin
Topics
  • Animals
  • Annexin A1 (immunology, metabolism)
  • Anti-Inflammatory Agents (immunology)
  • Humans
  • Inflammation (immunology)
  • Macrophages (immunology, metabolism)
  • Male
  • Mice
  • Mice, Knockout
  • Neutrophils (metabolism)
  • Peptides (immunology)
  • Phagocytosis (immunology)
  • Receptors, Formyl Peptide (agonists, immunology)
  • Receptors, Lipoxin (agonists, immunology)

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