| First Author | Dalli J | Year | 2013 |
| Journal | J Immunol | Volume | 190 |
| Issue | 12 | Pages | 6478-87 |
| PubMed ID | 23686496 | Mgi Jnum | J:204838 |
| Mgi Id | MGI:5543543 | Doi | 10.4049/jimmunol.1203000 |
| Citation | Dalli J, et al. (2013) Proresolving and tissue-protective actions of annexin A1-based cleavage-resistant peptides are mediated by formyl peptide receptor 2/lipoxin A4 receptor. J Immunol 190(12):6478-87 |
| abstractText | 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 approximately 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 ( approximately 25-45%), and stimulated neutrophil apoptosis and macrophage efferocytosis ( approximately 45%). In murine cardiac ischemia/reperfusion injury, CR-AnxA1(2-50) elicited tissue-protective actions reducing infarct size ( approximately 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. |
