Signaling pathways of the TREM-1- and TLR4-mediated neutrophil oxidative burst.
The triggering receptor expressed on myeloid cells 1 (TREM-1) is involved in the innate inflammatory response to microbial infections. Activation and expression of TREM-1 by polymorphonuclear neutrophils (PMN) occurs in concert with Toll-like receptors (TLR) such as TLR4 for bacterial lipopolysaccharide. However, it is currently unclear how this is mediated on a molecular level. Using pharmacological inhibitors and Western blot analysis we demonstrate that phosphatidyl inositide 3-kinase, phospholipase C and the mitogen-activated kinase p38MAPK are essential for the TREM-1- and TLR4-induced oxidative burst of human PMN. The activation of protein kinase B and extracellular signal-related kinase show characteristic phosphorylation patterns upon single or co-ligation indicating individual activation pathways of both receptors. Taken together, we provide new insights into the mechanisms how TREM-1 and TLR interact creating synergistic activation in PMN. These results shed a new light on our understanding of how the innate inflammatory responses are regulated and might contribute to the development of future concepts for the treatment of severe inflammatory conditions such as sepsis.
Haselmayer
Philipp
P
Institute for Immunology, Johannes Gutenberg University, Mainz, Germany.
Daniel
Martin
M
Tertilt
Christine
C
Salih
Helmut R
HR
Stassen
Michael
M
Schild
Hansjörg
H
Radsak
Markus P
MP
D015153:Blotting, Western; D002469:Cell Separation; D004789:Enzyme Activation / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D008958:Models, Molecular; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism*; D016897:Respiratory Burst / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism*; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism
D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C495345:TLR4 protein, human; C408842:TREM1 protein, human; D051197:Toll-Like Receptor 4; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases