An Annexin 1 N-Terminal Peptide Activates Leukocytes by Triggering Different Members of the Formyl Peptide Receptor Family

Abstract

The human N-formyl peptide receptor (FPR) is a key modulator of chemotaxis directing granulocytes toward sites of bacterial infections. FPR is the founding member of a subfamily of G protein-coupled receptors thought to function in inflammatory processes. The other two members, FPR-like (FPRL)1 and FPRL2, have a greatly reduced affinity for bacterial peptides or do not bind them at all, with FPRL2 being considered an orphan receptor so far. In this study we show that a peptide derived from the N-terminal domain of the anti-inflammatory protein annexin 1 (lipocortin 1) can activate all three FPR family members at similar concentrations. The annexin 1 peptide initiates chemotactic responses in human monocytes that express all three FPR family members and also desensitizes the cells toward subsequent stimulation with bacterial peptide agonists. Experiments using HEK 293 cells stably expressing a single FPR family member reveal that all three receptors can be activated and desensitized by the N-terminal annexin 1 peptide. These observations identify the annexin 1 peptide as the first endogenous ligand of FPRL2 and indicate that annexin 1 participates in regulating leukocyte emigration into inflamed tissue by activating and desensitizing different receptors of the FPR family.

Proresolving and Tissue-Protective Actions of Annexin A1–Based Cleavage-Resistant Peptides Are Mediated by Formyl Peptide Receptor 2/Lipoxin A4 Receptor

“…This suggests that the active conformation of the pharmacophore residing in the AnxA1 N terminus, which is exposed when the protein changes conformation upon binding to calcium and acidic phospholipids (36), is better retained in the 50-aa-long peptides. AnxA1 2-50 and CR-AnxA1 2-50 did not display specific binding toward human FPR1, in contrast with the shorter AnxA1-derived peptides that bind with low affinity (low micromolar range) to both FPR1 and FPR2/ALX (4,21). Of note, the finding that these peptides are bioactive at concentrations lower than the ones required for the displacement curves in binding assay is an apparent discrepancy that arises from the use of a heterogeneous tracer, a feature already noted for the parent protein AnxA1 (4).…”

“…19). The reduced potency displayed by short AnxA1 peptides is attributable to low binding affinity to the AnxA1 receptor and lack of receptor specificity, because they bind with similar potency the cognate receptor FPR1 (20,21). In this study, we investigate the bioactions of AnxA1-derived peptides that span the full N-terminal region and present evidence for their FPR2/ALX-specific, potent antiinflammatory, proresolving, and tissue-protective actions.…”

Anti-inflammatory functions of glucocorticoid-induced genes

“…AnxA1 is relocalized from the cytoplasm to the plasma membrane in response to a variety of agonists including GCs, and can be externalized or secreted via an uncharacterized mechanism. The N-terminus of AnxA1, which is distinct from those of other annexins, is thought to exert anti-inflammatory effects by signalling through members of the formyl peptide receptor (FPR) family, in particular FPRL1 (Ernst et al, 2004;Gavins et al, 2003;Hayhoe et al, 2006;John et al, 2007;Perretti et al, 2001;Walther et al, 2000). This cell surface receptor also recognizes as a ligand lipoxin A 4 , a prostanoid involved in the resolution of inflammation.…”

FAM19A4 is a novel cytokine ligand of formyl peptide receptor 1 (FPR1) and is able to promote the migration and phagocytosis of macrophages

“…[29][30][31] As the endogenous ligand of FPR1, the N-terminal peptide Ac2-26 is cleaved from Annexin-1 during inflammation and epithelial wound healing. 32 All the known ligands are passively released to activate the host immune responses when infections occur. FAM19A4 would be more important as a cytokine ligand for FPR1.…”