The neurotoxic prion peptide fragment PrP(106-126) is a chemotactic agonist for the G protein-coupled receptor formyl peptide receptor-like 1.
Prion diseases are transmissible and fatal neurodegenerative disorders which involve infiltration and activation of mononuclear phagocytes at the brain lesions. A 20-aa acid fragment of the human cellular prion protein, PrP(106-126), was reported to mimic the biological activity of the pathologic isoform of prion and activates mononuclear phagocytes. The cell surface receptor(s) mediating the activity of PrP(106-126) is unknown. In this study, we show that PrP(106-126) is chemotactic for human monocytes through the use of a G protein-coupled receptor formyl peptide receptor-like 1 (FPRL1), which has been reported to interact with a diverse array of exogenous or endogenous ligands. Upon stimulation by PrP(106-126), FPRL1 underwent a rapid internalization and, furthermore, PrP(106-126) enhanced monocyte production of proinflammatory cytokines, which was inhibited by pertussis toxin. Thus, FPRL1 may act as a "pattern recognition" receptor that interacts with multiple pathologic agents and may be involved in the proinflammatory process of prion diseases.
Le
Y
Y
Laboratory of Molecular Immunoregulation, Division of Basic Sciences, National Cancer Institute-Frederick, Science Applications International Corporation-Frederick, Frederick, MD 21702, USA.
Yazawa
H
H
Gong
W
W
Yu
Z
Z
Ferrans
V J
VJ
Murphy
P M
PM
Wang
J M
JM
D000818:Animals; D020013:Calcium Signaling / Q000276:immunology; D002460:Cell Line; D002630:Chemotactic Factors / Q000502:physiology* / Q000633:toxicity; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D017628:Microglia / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism*; D010446:Peptide Fragments / Q000819:agonists* / Q000502:physiology / Q000633:toxicity*; D011328:Prions / Q000819:agonists* / Q000502:physiology / Q000633:toxicity*; D051381:Rats; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic / Q000378:metabolism / Q000502:physiology*; D044067:Receptors, Lipoxin; D018000:Receptors, Peptide / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured
D002630:Chemotactic Factors; D016207:Cytokines; C105101:FPR2 protein, human; D008024:Ligands; D010446:Peptide Fragments; D011328:Prions; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic; D044067:Receptors, Lipoxin; D018000:Receptors, Peptide; C082632:prion protein (106-126); D009240:N-Formylmethionine Leucyl-Phenylalanine; D019204:GTP-Binding Proteins