Design and characterization of a cleavage-resistant Annexin A1 mutant to control inflammation in the microvasculature

Magali Pederzoli-Ribeil, Francesco Maione, Dianne Cooper, Adam Al-Kashi, Jesmond Dalli, Mauro Perretti, Fulvio D'Acquisto

Research output: Contribution to journalArticlepeer-review


Human polymorphonuclear leukocytes adhesion to endothelial cells during the early stage of inflammation leads to cell surface externalization of Annexin A1 (AnxA1), an effector of endogenous anti-inflammation. The antiadhesive properties of AnxA1 become operative to finely tune polymorphonuclear leukocytes transmigration to the site of inflammation. Membrane bound proteinase 3 (PR3) plays a key role in this microenvironment by cleaving the N terminus bioactive domain of AnxA1. In the present study, we generated a PR3-resistant human recombinant AnxA1-named superAnxA1 (SAnxA1)-and tested its in vitro and in vivo properties in comparison to the parental protein. SAnxA1 bound and activated formyl peptide receptor 2 in a similar way as the parental protein, while showing a resistance to cleavage by recombinant PR3. SAnxA1 retained anti-inflammatory activities in the murine inflamed microcirculation (leukocyte adhesion being the readout) and in skin trafficking model. When longer-lasting models of inflammation were applied, SAnxA1 displayed stronger anti-inflammatory effect over time compared with the parental protein. Together these results indicate that AnxA1 cleavage is an important process during neutrophilic inflammation and that controlling the balance between AnxA1/PR3 activities might represent a promising avenue for the discovery of novel therapeutic approaches.

Original languageEnglish
Pages (from-to)4288-96
Number of pages9
Issue number20
Publication statusPublished - 18 Nov 2010


  • Amino Acid Sequence
  • Animals
  • Annexin A1
  • Anti-Inflammatory Agents
  • Cell Adhesion
  • Cell Communication
  • Cell Movement
  • Endothelial Cells
  • Female
  • HEK293 Cells
  • Humans
  • Inflammation
  • Male
  • Mice
  • Microvessels
  • Molecular Sequence Data
  • Mutant Proteins
  • Neutrophils
  • Protein Binding
  • Protein Engineering
  • Receptors, Formyl Peptide
  • Receptors, Lipoxin
  • Recombinant Proteins
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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