Annexin A1 Counteracts Chemokine-Induced Arterial Myeloid Cell Recruitment
Rationale: Chemokine-controlled arterial leukocyte recruitment is a crucial process in atherosclerosis. Formyl-peptide receptor 2 (FPR2) is a chemoattractant receptor which recognizes pro-inflammatory and pro-resolving ligands. The contribution of FPR2 and its pro-resolving ligand Annexin A1 to atherosclerotic lesion formation is largely undefined.
Objective:Due to the ambivalence of FPR2 ligands, we here investigate the role of FPR2 and its resolving ligand Annexin A1 in atherogenesis.
Methods and Results: Deletion of FPR2 or its ligand Annexin A1 enhances atherosclerotic lesion formation, arterial myeloid cell adhesion, and recruitment. Mechanistically we identify Annexin A1 as an endogenous inhibitor of integrin activation evoked by the chemokines CCL5, CCL2, and CXCL1. Specifically, the Annexin A1 fragment Ac2-26 counteracts conformational activation and clustering of integrins on myeloid cells evoked by CCL5, CCL2, and CXCL1 through inhibiting activation of the small GTPase Rap1. In vivo administration of Ac2-26 largely diminishes arterial recruitment of myeloid cells in a FPR2-dependent fashion. This effect is also observed in presence of selective antagonists to CCR5, CCR2, or CXCR2, while Ac2-26 was without effect when all three chemokine receptors were antagonized simultaneously. Finally, repeated treatment with Ac2-26 reduces atherosclerotic lesion sizes and lesional macrophage accumulation.
Conclusions: Instructing the Annexin A1-FPR2 axis harbors a novel approach to target arterial leukocyte recruitment. With the ability of Ac2-26 to counteract integrin activation exerted by various chemokines, delivery of Ac2-26 may be superior in inhibition of arterial leukocyte recruitment as compared to blocking individual chemokine receptors.
- Received December 12, 2014.
- Revision received December 16, 2014.
- Accepted December 17, 2014.