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.

Design and characterization of a cleavage-resistant Annexin A1 mutant to control inflammation in the microvasculature / Pederzoli ribeil, Magali; Maione, Francesco; Cooper, Dianne; Al kashi, Adam; Dalli, Jesmond; Perretti, Mauro; D'Acquisto, Fulvio. - In: BLOOD. - ISSN 0006-4971. - 116:20(2010), pp. 4288-4296. [10.1182/blood-2010-02-270520]

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

MAIONE, FRANCESCO;D'ACQUISTO, FULVIO
2010

Abstract

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.
2010
Design and characterization of a cleavage-resistant Annexin A1 mutant to control inflammation in the microvasculature / Pederzoli ribeil, Magali; Maione, Francesco; Cooper, Dianne; Al kashi, Adam; Dalli, Jesmond; Perretti, Mauro; D'Acquisto, Fulvio. - In: BLOOD. - ISSN 0006-4971. - 116:20(2010), pp. 4288-4296. [10.1182/blood-2010-02-270520]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/691852
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