Mechanisms of increased expression of toll-like receptor-4 in human monocyte/macrophage-derived foam cells

Abstract Inflammatory bone loss in septic and inflammatory conditions is due to increased activity of osteoclasts that requires receptor activator of NF-kappa B-ligand (RANKL). Neutrophils are the predominant infiltrating cells in these conditions. Although disease severity is linked to neutrophils, their role in evolution of bony lesions is not clear. We show that lipopolysaccharide (LPS), a toll-like receptor 4 ligand, up-regulated the expression of membrane RANKL in human blood neutrophils and murine air pouch–derived neutrophils. LPS-activated human and murine neutrophils, cocultured with human monocyte-derived osteoclasts and RAW 264.7 cells, respectively, stimulated bone resorption. Transfection of PLB-985 neutrophil-like cells with RANKL antisense RNA reduced osteoclastogenesis. Synovial fluid neutrophils of patients with exacerbation of rheumatoid arthritis strongly expressed RANKL and activated osteoclastogenesis in coculture systems. Osteoprotegerin, the RANKL decoy receptor, suppressed osteoclast activation by neutrophils from these different sources. Moreover, direct cell-cell contact between neutrophils and osteoclasts was visualized by confocal laser microscopy. Activation of neutrophil membrane-bound RANKL was linked to tyrosine phosphorylation of Src-homology domain–containing cytosolic phosphatase 1 with concomitant down-regulation of cytokine production. The demonstration of these novel functions of neutrophils highlights their potential role in osteoimmunology and in therapeutics of inflammatory bone disease.

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Toll-like Receptor 4 Mediates Oxidized LDL-Induced Macrophage Differentiation to Foam Cells

Journal of Surgical Research ◽

10.1016/j.jss.2011.06.033 ◽

2011 ◽

Vol 171 (1) ◽

pp. e27-e31 ◽

Cited By ~ 56

Author(s):

Kenneth W. Howell ◽

Xianzhong Meng ◽

David A. Fullerton ◽

Chunhua Jin ◽

T. Brett Reece ◽

...

Keyword(s):

Oxidized Ldl ◽

Foam Cells ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Macrophage Differentiation

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Bisdemethoxycurcumin and Its Cyclized Pyrazole Analogue Differentially Disrupt Lipopolysaccharide Signalling in Human Monocyte-Derived Macrophages

Mediators of Inflammation ◽

10.1155/2018/2868702 ◽

2018 ◽

Vol 2018 ◽

pp. 1-13 ◽

Cited By ~ 3

Author(s):

Serena Tedesco ◽

Morena Zusso ◽

Laura Facci ◽

Annalisa Trenti ◽

Carlotta Boscaro ◽

...

Keyword(s):

Human Blood ◽

Inflammatory Responses ◽

Interleukin 1 ◽

Human Monocyte ◽

Signalling Pathways ◽

Toll Like Receptor ◽

Blood Monocytes ◽

Toll Like Receptor 4 ◽

Anti Inflammatory ◽

Macrophage Subset

Several studies suggest that curcumin and related compounds possess antioxidant and anti-inflammatory properties including modulation of lipopolysaccharide- (LPS-) mediated signalling in macrophage cell models. We here investigated the effects of curcumin and the two structurally unrelated analogues GG6 and GG9 in primary human blood-derived macrophages as well as the signalling pathways involved. Macrophages differentiated from peripheral blood monocytes for 7 days were activated with LPS or selective Toll-like receptor agonists for 24 h. The effects of test compounds on cytokine production and immunophenotypes evaluated as CD80+/CCR2+ and CD206+/CD163+ subsets were examined by ELISA and flow cytometry. Signalling pathways were probed by Western blot. Curcumin (2.5–10 μM) failed to suppress LPS-induced inflammatory responses. While GG6 reduced LPS-induced IκB-α degradation and showed a trend towards reduced interleukin-1β release, GG9 prevented the increase in proinflammatory CD80+ macrophage subset, downregulation of the anti-inflammatory CD206+/CD163+ subset, increase in p38 phosphorylation, and increase in cell-bound and secreted interleukin-1β stimulated by LPS, at least in part through signalling pathways not involving Toll-like receptor 4 and nuclear factor-κB. Thus, the curcumin analogue GG9 attenuated the LPS-induced inflammatory response in human blood-derived macrophages and may therefore represent an attractive chemical template for macrophage pharmacological targeting.

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Oligosaccharides of Hyaluronan Activate Dendritic Cells via Toll-like Receptor 4

Journal of Experimental Medicine ◽

10.1084/jem.20001858 ◽

2002 ◽

Vol 195 (1) ◽

pp. 99-111 ◽

Cited By ~ 928

Author(s):

Christian Termeer ◽

Frauke Benedix ◽

Jonathon Sleeman ◽

Christina Fieber ◽

Ursula Voith ◽

...

Keyword(s):

Dendritic Cells ◽

Map Kinases ◽

Nuclear Translocation ◽

Degradation Products ◽

Human Monocyte ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Functional Maturation ◽

Factor Α ◽

Necrosis Factor

Low molecular weight fragmentation products of the polysaccharide of Hyaluronic acid (sHA) produced during inflammation have been shown to be potent activators of immunocompetent cells such as dendritic cells (DCs) and macrophages. Here we report that sHA induces maturation of DCs via the Toll-like receptor (TLR)-4, a receptor complex associated with innate immunity and host defense against bacterial infection. Bone marrow–derived DCs from C3H/HeJ and C57BL/10ScCr mice carrying mutant TLR-4 alleles were nonresponsive to sHA-induced phenotypic and functional maturation. Conversely, DCs from TLR-2–deficient mice were still susceptible to sHA. In accordance, addition of an anti–TLR-4 mAb to human monocyte–derived DCs blocked sHA-induced tumor necrosis factor α production. Western blot analysis revealed that sHA treatment resulted in distinct phosphorylation of p38/p42/44 MAP-kinases and nuclear translocation of nuclear factor (NF)-κB, all components of the TLR-4 signaling pathway. Blockade of this pathway by specific inhibitors completely abrogated the sHA-induced DC maturation. Finally, intravenous injection of sHA-induced DC emigration from the skin and their phenotypic and functional maturation in the spleen, again depending on the expression of TLR-4. In conclusion, this is the first report that polysaccharide degradation products of the extracellular matrix produced during inflammation might serve as an endogenous ligand for the TLR-4 complex on DCs.

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Toll-like Receptor 4–Induced Glycolytic Burst in Human Monocyte-Derived Dendritic Cells Results from p38-Dependent Stabilization of HIF-1α and Increased Hexokinase II Expression

The Journal of Immunology ◽

10.4049/jimmunol.1701522 ◽

2018 ◽

Vol 201 (5) ◽

pp. 1510-1521 ◽

Cited By ~ 20

Author(s):

Laure Perrin-Cocon ◽

Anne Aublin-Gex ◽

Olivier Diaz ◽

Christophe Ramière ◽

Francesco Peri ◽

...

Keyword(s):

Dendritic Cells ◽

Human Monocyte ◽

Toll Like Receptor ◽

Hexokinase Ii ◽

Toll Like Receptor 4

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Phenol/water extract of Treponema socranskii subsp. socranskii as an antagonist of Toll-like receptor 4 signalling

Microbiology ◽

10.1099/mic.0.28470-0 ◽

2006 ◽

Vol 152 (2) ◽

pp. 535-546 ◽

Cited By ~ 14

Author(s):

Sung-Hoon Lee ◽

Kack-Kyun Kim ◽

In-Chul Rhyu ◽

Sukhoon Koh ◽

Dae-Sil Lee ◽

...

Keyword(s):

Water Extract ◽

Human Monocyte ◽

Antagonistic Activity ◽

Intercellular Adhesion Molecule ◽

Toll Like Receptor ◽

Intercellular Adhesion Molecule 1 ◽

Toll Like Receptor 4 ◽

E Coli ◽

Monocyte Cell ◽

Phenol Water

Treponema socranskii is one of the most frequently found oral spirochaetes in periodontitis and endodontic infections. LPS or glycolipids from bacteria are potent stimulators of innate immune and inflammatory systems. In this study the bioactivity of a phenol/water extract from T. socranskii subsp. socranskii (TSS-P) was analysed. TSS-P showed minimal endotoxicity and no inducing potential for proinflammatory cytokines (TNF-α and IL-8) or for intercellular adhesion molecule-1 (ICAM-1) in human monocyte cell line THP-1 cells and primary cultured human gingival fibroblasts. Rather, it inhibited ICAM-1 expression and IL-8 secretion from cells stimulated by the LPS of Escherichia coli and Actinobacillus actinomycetemcomitans, which are known to be Toll-like receptor 4 (TLR4) agonists. However, this antagonistic activity was not shown in cells stimulated by peptidoglycan or IL-1β. As its antagonistic mechanism, TSS-P blocked the binding of E. coli LPS to LPS-binding protein (LBP) and CD14, which are molecules involved in the recruitment of LPS to the cell membrane receptor complex TLR4–MD-2 for the intracellular signalling of LPS. TSS-P itself did not bind to MD-2 or THP-1 cells, but inhibited the binding of E. coli LPS to MD-2 or to the cells in the presence of serum (which could be replaced by recombinant human LBP and recombinant human CD14). The results suggest that TSS-P acts as an antagonist of TLR4 signalling by interfering with the functioning of LBP/CD14.

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