A new staphylococcal anti-inflammatory protein that antagonizes the formyl peptide receptor-like 1.
Bacteria have developed mechanisms to escape the first line of host defense, which is constituted by the recruitment of phagocytes to the sites of bacterial invasion. We previously described the chemotaxis inhibitory protein of Staphylococcus aureus, a protein that blocks the activation of neutrophils via the formyl peptide receptor (FPR) and C5aR. We now describe a new protein from S. aureus that impaired the neutrophil responses to FPR-like1 (FPRL1) agonists. FPRL1 inhibitory protein (FLIPr) inhibited the calcium mobilization in neutrophils stimulated with MMK-1, WKYMVM, prion-protein fragment PrP(106-126), and amyloid beta(1-42). Stimulation with low concentrations of fMLP was partly inhibited. Directed migration was also completely prevented toward MMK-1 and partly toward fMLP. Fluorescence-labeled FLIPr efficiently bound to neutrophils, monocytes, B cells, and NK cells. HEK293 cells transfected with human C5aR, FPR, FPRL1, and FPRL2 clearly showed that FLIPr directly bound to FPRL1 and, at higher concentrations, also to FPR but not to C5aR and FPRL2. FLIPr can reveal unknown inflammatory ligands crucial during S. aureus infections. As a novel described FPRL1 antagonist, it might lead to the development of therapeutic agents in FPRL1-mediated inflammatory components of diseases such as systemic amyloidosis, Alzheimer's, and prion disease.
Prat
Cristina
C
Eijkman-Winkler Institute, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
Bestebroer
Jovanka
J
de Haas
Carla J C
CJ
van Strijp
Jos A G
JA
van Kessel
Kok P M
KP
D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D003001:Cloning, Molecular; D006801:Humans; D018375:Neutrophil Activation / Q000276:immunology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D016133:Polymerase Chain Reaction; D044042:Receptors, Formyl Peptide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D044067:Receptors, Lipoxin / Q000037:antagonists & inhibitors*; D013211:Staphylococcus aureus
D000893:Anti-Inflammatory Agents; D001426:Bacterial Proteins; C105101:FPR2 protein, human; C516018:FPRL1 inhibitory protein, S aureus; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D002118:Calcium