Innate immune responses to TREM-1 activation: overlap, divergence, and positive and negative cross-talk with bacterial lipopolysaccharide.
TREM-1 (triggering receptor expressed on myeloid cells-1) is an orphan immunoreceptor expressed on monocytes, macrophages, and neutrophils. TREM-1 associates with and signals via the adapter protein DAP12/TYROBP, which contains an ITAM. TREM-1 activation by receptor cross-linking has been shown to be proinflammatory and to amplify some cellular responses to TLR ligands such as bacterial LPS. To investigate the cellular consequences of TREM-1 activation, we have characterized global gene expression changes in human monocytes in response to TREM-1 cross-linking in comparison to and combined with LPS. Both TREM-1 activation and LPS up-regulate chemokines, cytokines, matrix metalloproteases, and PTGS/COX2, consistent with a core inflammatory response. However, other immunomodulatory factors are selectively induced, including SPP1 and CSF1 (i.e., M-CSF) by TREM-1 activation and IL-23 and CSF3 (i.e., G-CSF) by LPS. Additionally, cross-talk between TREM-1 activation and LPS occurs on multiple levels. Although synergy in GM-CSF protein production is reflected in commensurate mRNA abundance, comparable synergy in IL-1beta protein production is not. TREM-1 activation also attenuates the induction of some LPS target genes, including those that encode IL-12 cytokine family subunits. Where tested, positive TREM-1 outputs are greatly reduced by the PI3K inhibitor wortmannin, whereas this attenuation is largely PI3K independent. These experiments provide a detailed analysis of the cellular consequences of TREM-1 activation and highlight the complexity in signal integration between ITAM- and TLR-mediated signaling.
Dower
Ken
K
Department of Inflammation, Wyeth Research, Cambridge, MA 02140, USA.
Ellis
Debra K
DK
Saraf
Kathryn
K
Jelinsky
Scott A
SA
Lin
Lih-Ling
LL
D002469:Cell Separation; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D020239:Receptor Cross-Talk / Q000276:immunology*; D011971:Receptors, Immunologic / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
D008070:Lipopolysaccharides; D011971:Receptors, Immunologic; C473366:TREML1 protein, human