Functional genomics of silencing TREM-1 on TLR4 signaling in macrophages

Ornatowska, Magdalena; Azim, Anser C.; Wang, X.; Christman, John W.; Xiao, Lü; Joo, Myung; Sadikot, Ruxana T.

doi:10.1152/ajplung.00140.2007

Cited by 114 publications

(111 citation statements)

References 36 publications

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“…We have shown that silencing of TREM-1 gene significantly altered expression of several genes, including MyD88, CD14, IkBa, IL-1b, MCP-1, and IL-10 in response to treatment with LPS in macrophage [24,25]. Thus, it is evident that TREM-1 may amplify the responses of both TLR and NLR in response to microbial products.…”

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confidence: 92%

MYD88‐dependent and ‐independent activation of TREM‐1 via specific TLR ligands

et al. 2009

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Triggering receptor expressed on myeloid cells (TREM)-1 plays an important role in myeloid cell-activated inflammatory responses. Although TLR ligands such as LPS and lipoteichoic acid have been shown to upregulate TREM-1 expression in macrophage and neutrophils, the role of specific TLR in inducing the expression of TREM-1 remains unclear. In this study, we investigated whether the presence of TLR is necessary for the expression of TREM-1. We show that BM-derived macrophages from TLR4 and TLR2 KO mice failed to induce expression of TREM-1 message and protein in response to their specific ligands. Interestingly, the expression of TREM-1 in response to LPS is not altered in myeloid differentiation factor 88 (MyD88) KO macrophages, suggesting that downstream of TLR a MyD88-independent pathway induces the expression of TREM-1. Inhibiting toll/IL-1R domain-containing adaptor-inducing IFN-b (TRIF) expression by siRNA decreased TREM-1 expression in response to LPS, suggesting that the expression of TREM-1 in response to LPS was mediated by the TRIF signaling pathway. On the other hand, the expression of TREM-1 in response to lipoteichoic acid is dependent on MyD88 expression. These data indicate that the expression of TREM-1 in response to TLR ligands occurs secondary to downstream signaling events and that the presence of TLR is necessary for the expression of TREM-1 in response to their specific ligands. However, the downstream signaling required for the expression of TREM-1 is dependent on the stimulus and the surface receptor through which the signaling is initiated.Key words: Innate immunity . TLR . TREM-1 IntroductionTriggering receptor expressed on myeloid cells 1 (TREM-1) belongs to the TREM super-family of receptors, which is expressed on monocytes and neutrophils [1][2][3][4][5]. These receptors activate downstream signaling pathways with the help of an adaptor molecule, DAP12 [2]. Although the natural ligands for TREM-1 have not been identified the engagement of TREM-1 synergizes with the effects of the TLR ligands and amplifies the synthesis of inflammatory cytokines [2][3][4]6]. Because blocking of TREM-1 improves the survival of mice with bacterial sepsis TREM-1 has been perceived to play an essential role in acute inflammatory responses in murine models of septic shock [2,[7][8][9][10][11][12][13].In the presence of infection, inflammation is triggered through the recognition of microorganism-by the pathogen associated molecules such as the TLR, which are expressed on the surface of innate immune cells such as monocytes, macrophages, and dendritic cells [14][15][16]. To date ten members of TLR have been identified in human, and 13 in mice, and a series of genetic series have revealed their respective ligands. On engagement with 162ligands, TLR recruit specific adapter molecules that propagate downstream signaling [17]. This interaction then leads to the activation of NF-kB and to the release of pro-inflammatory TNF-a, IL-12, IL-1, IL-6, IL-8, and anti-inflammatory (IL-10 and TGF-b) cytokines [18]. TLR ...

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confidence: 92%

MYD88‐dependent and ‐independent activation of TREM‐1 via specific TLR ligands

et al. 2009

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“…A crucial role of TREM-1 has initially been demonstrated in the development of septic shock (Bouchon et al, 2001;Gibot et al, 2004b). TREM-1 activation and expression occurs synergistically with TLRs (Arts et al, 2011;Klesney-Tait and Colonna, 2007;Klesney-Tait et al, 2006), as the TREM family contains both inhibitory and activating receptors capable of modulating the signaling downstream of TLRs (Allcock et al, 2003;Ornatowska et al, 2007). Moreover, TREM-1 has also been associated with NOD-Like Receptors (NLR), responsible for sensing microbial danger signals and amplifying the inflammatory response (El Mezayen et al, 2007;Netea et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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

Bostancı

Thurnheer

Belibasakis

2011

Molecular Immunology

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Porphyromonas gingivalis, is a Gram-negative obligate oral anaerobic bacterium highly implicated in periodontal disease, the most prevalent chronic inflammatory disease, but recent evidence also indicates a potential contribution to systemic inflammation. The Triggering Receptor Expressed on Myeloid cells 1 (TREM-1) is a cell surface receptor of the immunoglobulin superfamily, which, along with its adaptor signalling molecule DAP12, is involved in immune response to bacterial and fungal infections, particularly by amplifying the production of pro-inflammatory cytokines by the host. The aim of the present study was to investigate the effect of P. gingivalis on the expression of the TREM-1/DAP12 pathway, as well as its engagement in pro-inflammatory cytokine production, by the myelomonocytic cell line MonoMac-6. P. gingivalis enhanced TREM-1 gene expression by the cells, concomitantly to an increase of soluble TREM-1 secretion. Engagement of TREM-1, by introducing anti-TREM-1 to the experimental system, resulted in further potentiation of the pro-inflammatory responses to P. gingivalis, as evaluated by a further enhancement of interleukin (IL)-1 and IL-6 secretion. On the contrary, the synthetic TREM-1 antagonist LP17 reduced the P. gingivalis-induced IL-1 and IL-6 secretion by approximately 50%. In conclusion, the putative periodontal pathogen P. gingivalis can positively regulate the expression of the TREM-1/DAP12 pathway in monocytic cells. Moreover, engagement of TREM-1 can further potentiate the pro-inflammatory responses to P. gingivalis infection. This effect may contribute not only to the pathogenesis of inflammatory periodontal disease, but also to the enhancement of systemic inflammation.

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“…Following ligation it associates with a signal transduction molecule, DAP12, triggering that initiates the secretion of inflammatory cytokines. TREM-1 has emerged as an important amplifier of TLR-in- duced inflammatory responses activating transcription factors that regulate the expression of proinflammatory cytokines and chemokines (14,16). This study provides yet another mechanism by which TREM-1 can perpetuate inflammation by inhibiting apoptosis of macrophage by activating the key anti-apoptotic proteins of the Bcl-2 family.…”

Section: Discussionmentioning

confidence: 87%

“…We have shown that the functional consequences of TREM-1 silencing in macrophages include an altered availability of key signaling (CD14, IB␣, and MyD88), and effector molecules (MCP-1, IL-1␤, and IL-6) downstream of TLR activation. Furthermore, the presence of TLRs is necessary for the expression of TREM-1 in response to specific TLR ligands (15)(16)(17). These receptors have thus emerged as potent amplifiers of TLR-initiated inflammatory responses (14,16,18).…”

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confidence: 99%

“…Furthermore, the presence of TLRs is necessary for the expression of TREM-1 in response to specific TLR ligands (15)(16)(17). These receptors have thus emerged as potent amplifiers of TLR-initiated inflammatory responses (14,16,18). Recent studies have shown that TREM-1 is highly expressed in tumor-associated tissue macrophages in colon, hepatocellular, and lung carcinoma (19 -22).…”

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confidence: 99%

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