A Seven-transmembrane, G Protein–coupled Receptor, FPRL1, Mediates the Chemotactic Activity of Serum Amyloid A for Human Phagocytic Cells

Abstract

We have previously reported (Badolato, R., J.M. Wang, W.J. Murphy, A.R. Lloyd, D.F. Michiel, L.L. Bausserman, D.J. Kelvin, and J.J. Oppenheim. 1994. J. Exp. Med. 180:203; Xu, L., R. Badolato, W.J. Murphy, D.L. Longo, M. Anver, S. Hale, J.J. Oppenheim, and J.M. Wang. 1995. J. Immunol. 155:1184.) that the acute phase protein serum amyloid A (SAA) is a potent chemoattractant for human leukocytes in vitro and mouse phagocytes in vivo. To identify the signaling mechanisms, we evaluated patterns of cross-desensitization between SAA and other leukocyte chemoattrctants. We found that the chemotactic bacterial peptide, N-formyl- methionyl-leucyl-phenylalanine (fMLP), was able to specifically attenuate Ca2+ mobilization in human phagocytes induced by SAA, but only at very high concentrations, suggesting that SAA uses a low affinity fMLP receptor. Here we demonstrate that SAA selectively induced Ca2+ mobilization and migration of HEK cells expressing FPRL1, a human seven-transmembrane domain phagocyte receptor with low affinity for fMLP, and high affinity for lipoxin A4. Furthermore, radiolabeled SAA specifically bound to human phagocytes and FPRL1-transfected 293 cells. In contrast, SAA was not a ligand or agonist for FPR, the high affinity fMLP receptor. Thus, SAA is the first chemotactic ligand identified for FPRL1. Our results suggest that FPRL1 mediates phagocyte migration in response to SAA.

Pleiotropic regulation of macrophage polarization and tumorigenesis by formyl peptide receptor-2

“…On the other hand, by binding other ligands such as SAA and cathelicidin LL-37, FPR2 also assumes a proinflammatory role such as chemoattraction and activation of human neutrophils, monocytes and T cells, and amplification of innate and adaptive immune responses, thereby modulating chemoattraction, dendritic cell differentiation, mast cell degranulation and angiogenesis stimulation (Su et al, 1999;De et al, 2000). Hence, it is a highly controversial receptor that regulates inflammation and immunity.…”

“…Radioiodinated SAA ( 125 I-labeled) was prepared by SAIC Frederick (NCI-FCRDC, Frederick, MD, USA). The experiments were performed as described previously by Su et al (1999). Briefly,…”

Serum Amyloid A Induces Monocyte Tissue Factor

“…However, at higher concentrations, SAA displaces apolipoprotein A-I (ApoA-I) yielding fractions containing SAA, lipid-poor ApoA-I, and lipoprotein-free SAA (11). The lipid-poor form has numerous proinflammatory actions, including chemotactic activity via binding the human N-formyl peptide receptor like-1 expressed on phagocytes (12), and can bind the extracellular matrix and induce matrix metalloproteases and proinflammatory cytokines (13)(14)(15).…”

Aspirin-Triggered Lipoxins Override the Apoptosis-Delaying Action of Serum Amyloid A in Human Neutrophils: A Novel Mechanism for Resolution of Inflammation

“…For instance, SAA facilitates reverse transport of cholesterol (10) and opsonizes bacteria (11), but it is also precursor of amyloid A, the deposit of which causes amyloidosis (3). SAA is chemotactic to polymorphonuclear leukocytes (PMN) and monocytes (12,13), regulates L-selectin and CD11b expression on leukocytes (13), promotes PMN adhesion to endothelial cells (13), and stimulates cytokine release from PMN (14,15). PMN activation is intimately linked to prolonged survival.…”

“…The in vitro actions of SAA are mediated through the G proteincoupled formyl peptide receptor-like 1/lipoxin A 4 (LXA 4 ) receptor (ALX) (12,15,22). ALX is a pleiotropic receptor that binds a variety of ligands including the glucocorticoid-inducible protein annexin-1 and the anti-inflammatory lipids LXA 4 and aspirin-triggered 15-epi-LXA 4 (22,23).…”