Effects of <i>Porphyromonas gingivalis </i><scp>LPS</scp> and <scp>LR</scp>12 peptide on <scp>TREM</scp>‐1 expression by monocytes

Dubar, Marie; Carrasco, Kévin; Gibot, Sébastien; Bisson, Catherine

doi:10.1111/jcpe.12925

Cited by 13 publications

(7 citation statements)

References 35 publications

(48 reference statements)

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“…Our present data are also consistent with a recent in vitro study, demonstrating that the LR12 TREM-1 inhibitor LR12 could prevent monocytic activation by P. gingivalis LPS [40], as well as our earlier in vitro findings demonstrating that LP17 can reduce cytokine release by monocytes in response to P. gingivalis whole bacteria [20,21]. Moreover, an earlier study in a psoriasis model showed that TREM-1 blockade in vitro and ex vivo significantly reduced the number of Th17 cells and decreased the secretion of IL-17, suggesting that TREM-1 positively regulates Th17 responses [41].…”

Section: Discussionsupporting

confidence: 93%

TREM-1 Is Upregulated in Experimental Periodontitis, and Its Blockade Inhibits IL-17A and RANKL Expression and Suppresses Bone loss

Bostancı

Abe

Belibasakis

et al. 2019

JCM

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Aim: Triggering receptor expressed on myeloid cells-1 (TREM-1) is a modifier of local and systemic inflammation. There is clinical evidence implicating TREM-1 in the pathogenesis of periodontitis. However, a cause-and-effect relationship has yet to be demonstrated, as is the underlying mechanism. The aim of this study was to elucidate the role of TREM-1 using the murine ligature-induced periodontitis model. Methods: A synthetic antagonistic LP17 peptide or sham control was microinjected locally into the palatal gingiva of the ligated molar teeth. Results: Mice treated with the LP17 inhibitor developed significantly less bone loss as compared to sham-treated mice, although there were no differences in total bacterial load on the ligatures. To elucidate the impact of LP17 on the host response, we analyzed the expression of a number of immune-modulating genes. The LP17 peptide altered the expression of 27/92 genes ≥ two-fold, but only interleukin (IL)-17A was significantly downregulated (4.9-fold). Importantly, LP17 also significantly downregulated the receptor activator of nuclear factor kappa-B-ligand (RANKL) to osteoprotegerin (OPG) ratio that drives osteoclastic bone resorption in periodontitis. Conclusion: Our findings show for the first time that TREM-1 regulates the IL-17A-RANKL/OPG axis and bone loss in experimental periodontitis, and its therapeutic blockade may pave the way to a novel treatment for human periodontitis.

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Section: Discussionsupporting

confidence: 93%

TREM-1 Is Upregulated in Experimental Periodontitis, and Its Blockade Inhibits IL-17A and RANKL Expression and Suppresses Bone loss

Bostancı

Abe

Belibasakis

et al. 2019

JCM

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“…The TREM-1 inflammatory signaling pathway is stimulated by periodontal pathogens in immune cells, propagating proinflammatory responses (Bostanci et al 2011; Bostanci and Belibasakis 2012; Willi et al 2014; Dubar et al 2018). However, the regulation of the TREM-1 pathway during development of gingival inflammation in response to dental biofilm accumulation is unknown.…”

Section: Discussionmentioning

confidence: 99%

“…TREM-1 itself is a transmembrane glycoprotein receptor of the immunoglobulin superfamily on neutrophils and monocytes (Gibot and Cravoisy 2004), which can also be secreted as a soluble protein into human body fluids through proteolytic cleavage by matrix metalloproteinases, and its putative ligand is shown to be peptidoglycan recognition protein 1 (PGLYRP1), recently associated with TREM-1 in periodontitis (Read et al 2015; Tammaro et al 2016; Nylund et al 2018). Periodontal pathogens can also regulate TREM-1 expression in immune cells in a manner that amplifies the proinflammatory responses, such as interleukin (IL)–1β (Bostanci et al 2011; Bostanci and Belibasakis 2012; Willi et al 2014; Dubar et al 2018). An important role of the TREM-1 signaling pathway is to fine-tune the immune system.…”

Section: Introductionmentioning

confidence: 99%

Regulation of PGLYRP1 and TREM-1 during Progression and Resolution of Gingival Inflammation

Silbereisen

Hallak

Nascimento

et al. 2019

JDR Clinical & Translational Research

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Introduction: The triggering receptor expressed on myeloid cells 1 (TREM-1) signaling pathway is stimulated by bacteria and, together with its putative ligand peptidoglycan recognition protein 1 (PGLYRP1), propagates proinflammatory responses. Objectives: We aimed to evaluate the TREM-1/PGLYRP1/interleukin (IL)–1β regulation in response to biofilm accumulation and removal in an experimental human gingivitis model. Methods: The study (n = 42 participants, mean age: 23.8 ± 3.7 y) comprised a recruitment step (day –14) followed by experimentally induced biofilm formation (induction [I] phase, day 0 to +21) and a 2-wk resolution (R) phase (day +21 to +35). Plaque was recorded by the Modified Quigley and Hein Plaque Index (TQHPI), while records of gingival inflammation were based on the Modified Gingival Index (MGI). Unstimulated whole saliva supernatants (n = 210, 5 time points) were tested for TREM-1, PGLYRP1, and IL-1β by enzyme-linked immunosorbent assay. Results: During the I-phase, concentrations of all analytes showed a tendency for downregulation at day +7 compared to day 0. TREM-1 (P = 0.019) and PGLYRP1 (P = 0.007) increased significantly between day +7 and day +21. Although all analyte levels decreased during the R-phase, the difference was not significant except TREM-1 being at borderline significance (P = 0.058). Moreover, TREM-1, PGLYRP1, and IL-1β showed significant positive correlations (P < 0.0001) with each other. The study participants were grouped into “fast” and “slow” responders based on clinical gingival inflammation scores. At each time point, fast responders showed significantly higher concentrations of TREM-1 (P < 0.025), PGLYRP1 (P < 0.007), and IL-1β (P < 0.025) compared to slow responders. Mixed-effects multilevel regression analyses revealed that PGLYRP1 (P = 0.047) and IL-1β (P = 0.005) showed a significant positive association with the MGI scores. Conclusion: The study demonstrated that TREM-1 and PGLYRP1 are regulated in response to biofilm accumulation and removal, and fast responders demonstrated higher levels of these analytes compared to slow responders. Knowledge Transfer Statement: The results of this study demonstrated the suitability of salivary TREM-1 and PGLYRP1 to reflect biofilm accumulation and removal and PGLYRP1 to monitor the progression and resolution of inflammation in gingivitis-susceptible individuals (fast responders). Combined with conventional risk factors, the molecular toolbox proposed here should be further validated in future studies to confirm whether it can be used for population-based monitoring and prevention of gingivitis.

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“…The mRNA levels of TREM-1, not TREM-2, were significantly increased in WARS1-treated J774.1 cells in time-dependent ( Figure 2 a) and dose-dependent manner ( Figure 2 b). LPS served as a positive control [ 15 ]. Protein levels of intracellular TREM-1, as well as of the secreted soluble form, were remarkably elevated by WARS1 after 8 h treatment ( Figure 2 c).…”

Section: Resultsmentioning

confidence: 99%

Tryptophanyl-tRNA Synthetase 1 Signals Activate TREM-1 via TLR2 and TLR4

et al. 2020

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Tryptophanyl-tRNA synthetase 1 (WARS1) is an endogenous ligand of mammalian Toll-like receptors (TLR) 2 and TLR4. Microarray data, using mRNA from WARS1-treated human peripheral blood mononuclear cells (PBMCs), had indicated WARS1 to mainly activate innate inflammatory responses. However, exact molecular mechanism remains to be understood. The triggering receptor expressed on myeloid cells (TREM)-1 is an amplifier of pro-inflammatory processes. We found WARS1 to significantly activate TREM-1 at both mRNA and protein levels, along with its cell surface expression and secretion in macrophages. WARS1 stimulated TREM-1 production via TLR2 and TLR4, mediated by both MyD88 and TRIF, since targeted deletion of TLR4, TLR2, MyD88, and TRIF mostly abrogated TREM-1 activation. Furthermore, WARS1 promoted TREM-1 downstream phosphorylation of DAP12, Syk, and AKT. Knockdown of TREM-1 and inhibition of Syk kinase significantly suppressed the activation of inflammatory signaling loop from MyD88 and TRIF, leading to p38 MAPK, ERK, and NF-κB inactivation. Finally, MyD88, TRIF, and TREM-1 signaling pathways were shown to be cooperatively involved in WARS1-triggered massive production of IL-6, TNF-α, IFN-β, MIP-1α, MCP-1, and CXCL2, where activation of Syk kinase was crucial. Taken together, our data provided a new insight into WARS1′s strategy to amplify innate inflammatory responses via TREM-1.

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Effects of Porphyromonas gingivalis LPS and LR12 peptide on TREM‐1 expression by monocytes

Abstract: TREM-1 inhibitors such as LR12 could be interesting for the modulation of the excessive inflammatory response that occurs during periodontal disease.

Cited by 13 publications

References 35 publications

TREM-1 Is Upregulated in Experimental Periodontitis, and Its Blockade Inhibits IL-17A and RANKL Expression and Suppresses Bone loss

TREM-1 Is Upregulated in Experimental Periodontitis, and Its Blockade Inhibits IL-17A and RANKL Expression and Suppresses Bone loss

Regulation of PGLYRP1 and TREM-1 during Progression and Resolution of Gingival Inflammation

Tryptophanyl-tRNA Synthetase 1 Signals Activate TREM-1 via TLR2 and TLR4

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