Innate Immune Responses to TREM-1 Activation: Overlap, Divergence, and Positive and Negative Cross-Talk with Bacterial Lipopolysaccharide

Abstract

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-1β 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.

Involvement of the TREM-1/DAP12 pathway in the innate immune responses to Porphyromonas gingivalis

“…Nevertheless, in another study it was demonstrated that E. coli LPS does not affect TREM-1 transcription in peripheral blood monocytes, but causes an increase in cell surface TREM-1 expression, denoting an effect on post-transcriptional modulation (Wong-Baeza et al, 2006). These seemingly conflicting results could be partly explained by recent evidence using microarray technology, suggesting that there is both positive and negative cross-talk between LPS and TREM-1 signalling in human monocytes (Dower et al, 2008). Moreover, Salmonella abortus LPS was shown to cause a transient increase of cell-surface TREM-1 at 6 h, succeeded by an increase of sTREM-1 at 24 h (Gomez-Pina et al, 2007).…”

“…Since the TREM-1 / DAP12 signalling pathway can amplify inflammation, and since it overlaps, in both positive and negative cross-talks with pathways known to be activated by P. gingivalis (Dower et al, 2008;Pathirana et al, 2010), there is merit to investigate whether and how this species may regulate the expression of TREM-1 / DAP12.…”

Gene Expression Profiling in Blood Provides Reproducible Molecular Insights into Asthma Control

“…One of the most compelling was the apparent activation of the TREM-1 (and related LPS) signaling pathway in subjects with suboptimal asthma control. Enrichment was noted for six gene sets that were differentially expressed in circulating murine monocytes in response to stimulation with TREM-1, LPS, or both (30). TREM-1 is a critical amplifier of inflammatory responses induced by tolllike receptor 4 (27) and other patternrecognition receptors (28,29).…”

“…Expressed on monocytes, macrophages, and neutrophils, TREM-1 is an orphan immunoreceptor that amplifies inflammation induced by patternrecognition receptors (28) and interacts with the toll-like receptor 4 to promote LPS-mediated granulocytic inflammation (27,29). These two molecules were represented by six replicated gene sets enriched during suboptimal control that came from the C7 subcollection GSE9988 ("Innate immune responses to TREM-1 activation") (see Table E4), which consists of profiles derived from a study of monocyte gene expression following treatment with either a TREM-1 activating antibody, LPS, or both (30).…”

Triggering receptor expressed on myeloid cells -1 as a new therapeutic target during inflammatory diseases

“…20,21 The activation of these pathways ultimately leads to a mobilization of intracellular calcium, a rearrangement of the actin cytoskeleton and activation of transcriptional factors such as NFκB. This finally results in production of metalloproteases, 22 pro-inflammatory cytokines and chemokines, [11][12][13]16,23 including MCP-1, MIP1-α, IL-1β, IL-6, IL-8, TNFα, along with rapid neutrophil degranulation and oxidative burst, 12,21 with a parallel negative regulation of anti-inflammatory IL-10. 16 Of note, although crystallographic analyses 24,25 can predict TREM-1 recognition by using antibody-equivalent complementary determining regions (CDR) loops (such as TCRs, CD8 and CTLA-4), its natural ligand has yet to be determined.…”