Functional and physical interactions between formyl-peptide-receptors and scavenger receptor MARCO and their involvement in amyloid beta 1-42-induced signal transduction in glial cells.
Recent studies suggest that the chemotactic G protein-coupled receptor formyl-peptide-receptor-like-1 (FPRL1) or the scavenger receptor MARCO (macrophage receptor with collagenous structure) plays an essential role in the inflammatory response of host defense mechanisms and neurodegenerative disorders such as Alzheimer's disease. We therefore analyzed the involvement of FPRL1 and MARCO in amyloid beta1-42 (Abeta1-42)-induced signalling by extracellular-signal regulated kinases 1/2 (ERK1/2) phosphorylation and cAMP level measurement in glial cells (astrocytes and microglia) and in transfected HEK293 cells. Receptors were inhibited by small interference RNA and the consequences in Abeta1-42- and MARCO agonist fucoidan-induced signal transduction were determined. Receptor deactivation by antagonists or small interference RNA verified the importance of FPRL1 for Abeta1-42-mediated signal transduction by ERK1/2 phosphorylation and cAMP level measurement in glial cells. Furthermore, for the first time, we have demonstrated a functional interaction between FPRL1 and scavenger receptors in fucoidan-mediated signalling by ERK1/2 phosphorylation and cAMP level measurement. In addition, co-immunoprecipitation data and fluorescence microscopy measurements revealed a physical interaction between FPR, FPRL1 and MARCO. These results suggest that FPRL1 plays a pivotal role for Abeta1-42-induced signal transduction in glial cells and the interaction with MARCO could explain the broad ligand spectrum of formyl peptide receptors.
Department of Anatomy and Cell Biology, RWTH Aachen University, Aachen, Germany. lbrandenburg@ukaachen.de
Lars-Ove
LO
Brandenburg
Maximilian
M
Konrad
Christoph J
CJ
Wruck
Thomas
T
Koch
Ralph
R
Lucius
Thomas
T
Pufe
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008856:Microscopy, Fluorescence; D009457:Neuroglia / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation; D010957:Plasmids / Q000235:genetics; D011134:Polysaccharides / Q000494:pharmacology; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D034741:RNA, Small Interfering / Q000235:genetics; D044042:Receptors, Formyl Peptide / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011971:Receptors, Immunologic / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D044067:Receptors, Lipoxin / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection
D016229:Amyloid beta-Peptides; C105101:FPR2 protein, human; C490460:MARCO protein, human; D010446:Peptide Fragments; D011134:Polysaccharides; D034741:RNA, Small Interfering; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic; D044067:Receptors, Lipoxin; C075222:amyloid beta-protein (1-42); D012313:RNA; C007789:fucoidan; D000242:Cyclic AMP; D048049:Extracellular Signal-Regulated MAP Kinases