Effects of TREM-1 activation in human neutrophils: activation of signaling pathways, recruitment into lipid rafts and association with TLR4.
Neutrophilic polymorphonuclears (PMNs) play an important role in the progression of sepsis-related inflammation and become highly activated by a wide array of ligands on the site. The triggering receptor expressed on myeloid cells-1 (TREM-1) is a recently described receptor that has many effects on human PMN. The engagement of TREM-1 on PMN can induce phagocytosis, reactive oxygen species production and release of myeloperoxidase and IL-8. LPS has a priming effect on these functions. We show in this paper that Lyn, AKT, extracellular signal-regulated kinase 1/2 and Jak2 signaling pathways are elicited following TREM-1 engagement and activation by a monoclonal agonist antibody (anti-TREM-1) in human PMN, leading to the phosphorylation of STAT5 and RelA, a subunit of the nuclear factor-kappa B family. We also show that TREM-1 is recruited to ganglioside M1-lipid rafts in PMN upon stimulation with LPS or anti-TREM-1. Moreover, we observed that Toll-like receptor 4 and TREM-1 co-localize upon stimulation and TREM-1 engagement resulted in the phosphorylation of IL-1R-associated kinase 1, but not its stimulant-induced degradation. These data shed a new light on how various receptors implicated in the innate immune response could interact to insure an efficient inflammatory response upon pathogens-associated aggression.
Fortin
Carl F
CF
Immunology Graduate Program, Clinical Research Center, Faculty of Medicine, University of Sherbrooke, Québec J1H 4C4, Canada.
Lesur
Olivier
O
Fulop
Tamas
T
D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D021962:Membrane Microdomains / Q000378:metabolism*; D009504:Neutrophils / Q000276:immunology*; D010766:Phosphorylation; D011971:Receptors, Immunologic / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D015854:Up-Regulation
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