Toll-like Receptor Activation of Human Cells by Synthetic Triacylated Lipid A-like Molecules

Dunn-Siegrist, Irène; Tissières, Pierre; Drifte, Geneviève; Bauer, Jacques; Moutel, Stéphane; Pugin, Jérôme

doi:10.1074/jbc.m112.348383

Cited by 16 publications

(13 citation statements)

References 40 publications

(35 reference statements)

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“…Epidemiological studies showed a correlation between immunological parameters and long-term survival in neoplastic patients [11]. Immunotherapeutic approaches based on the use of bacterial components such as the BCG or a lipid A derivative of LPS (OM-174-DP) have been proposed to increase the efficacy of standard treatments in different malignances including ovarian cancer [30,31]. It is of note however, that our present data, together with previous studies, suggest the existence of a complex tumor microenvironment that would impair the attack of immune effectors such as NK cells.…”

Section: Discussionmentioning

confidence: 99%

TLR activation of tumor‐associated macrophages from ovarian cancer patients triggers cytolytic activity of NK cells

et al. 2014

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We analyzed the functional outcome of the interaction between tumor-associated macrophages (TAMs) and natural killer (NK) cells. TAMs from ascites of ovarian cancer patients displayed an alternatively activated functional phenotype (M2) characterized by a remarkably high frequency and surface density of membrane-bound IL-18. Upon TLR engagement, TAMs acquired a classically activated functional phenotype (M1), released immunostimulatory cytokines (IL-12, soluble IL-18), and efficiently triggered the cytolytic activity of NK cells. TAMs also induced the release of IFN-γ from NK cells, which however was significantly lower compared with that induced by in vitro-polarized M2 cells. Most tumor-associated NK cells displayed a CD56 bright , CD16 neg or CD56 bright , CD16 dim phenotype, and very poor cytolytic activities, despite an increased expression of the activation marker CD69. They also showed downregulation of DNAM-1, 2B4, and NTB-A activating receptors, and an altered chemokine receptor repertoire. Importantly however, when appropriately stimulated, NK cells from the patients, including those cells isolated from ascites, efficiently killed autologous TAMs that expressed low, "nonprotective" levels of HLA class I molecules. Overall, our data show the existence of a complex tumor microenvironment in which poorly cytolytic/immature NK cells deal with immunosuppressive tumor-educated macrophages.Keywords: Human r Natural killer cells r Ovarian cancer r Tumor-associated macrophages Additional supporting information may be found in the online version of this article at the publisher's web-site [3][4][5][6]. Tumor and stromal cells produce chemokines such as CCL2 that recruit monocytes from peripheral blood. Once in tissue, the tumor microenvironment would prevent their differentiation into DCs while promoting differentiation into macrophages. Moreover, it would skew the macrophage polarization toward a proangiogenic/immunoregulatory M2-like phenotype with tumor-promoting properties. Notably, most studies have established a correlation between high numbers of tumorassociated macrophages (TAMs) within a tumor and poor prognosis [7][8][9]. Thus, an attractive novel clinical approach could be to identify factors able to revert TAMs into macrophages with M1 tumor-suppressive properties.Other innovative therapeutic protocols aim at increasing the function of immune effector cells with antitumor capabilities. Natural killer (NK) cells are appealing candidates for cancer immunotherapy [10,11] Results TAMs express high amounts of mIL-18TAMs were purified from ascitic fluids of patients affected by ovarian carcinoma (Table 1) and analyzed by flow cytometry for the expression of a large panel of cell surface markers ( Fig. 1 and Supporting Information Fig. 1). The results were compared with those obtained using in vitro IL-4-polarized M2 cells derived from peripheral blood monocytes of healthy donors. According to the gene expression profile analyses [19,20], the surface phenotype of TAMs closely resembled that of M2 cells (S...

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Section: Discussionmentioning

confidence: 99%

TLR activation of tumor‐associated macrophages from ovarian cancer patients triggers cytolytic activity of NK cells

et al. 2014

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“…The first step required for LPS to exert its direct BBB-disrupting effect is through binding to LPS receptors at the BBB, mainly mediated by the lipid A component of LPS (41). Therefore, the reason for the difference in the specific BBB-disrupting effect of S. enterica LPS relative to that of P. aeruginosa LPS may be differences in their structures, especially the lipid A component of LPS.…”

Section: Discussionmentioning

confidence: 99%

Species-Dependent Blood-Brain Barrier Disruption of Lipopolysaccharide: Amelioration by ColistinIn VitroandIn Vivo

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Nation

et al. 2013

Antimicrob Agents Chemother

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The aim of this study was to use in vitro and in vivo models to assess the impact of lipopolysaccharide (LPS) from two different bacterial species on blood-brain barrier (BBB) integrity and brain uptake of colistin. Following repeated administration of LPS from Pseudomonas aeruginosa, the brain-to-plasma ratio of [ 14 C]sucrose in Swiss outbred mice was not significantly increased. Furthermore, while the brain uptake of colistin in mice increased 3-fold following administration of LPS from Salmonella enterica, LPS from P. aeruginosa had no significant effect on colistin brain uptake. This apparent species-dependent effect did not appear to correlate with differences in plasma cytokine levels, as the concentrations of tumor necrosis factor alpha and interleukin-6 following administration of each LPS were not different (P > 0.05). To clarify whether this species-specific effect of LPS was due to direct effects on the BBB, human brain capillary endothelial (hCMEC/D3) cells were treated with LPS from P. aeruginosa or S. enterica and claudin-5 expression was measured by Western blotting. S. enterica LPS significantly (P < 0.05) reduced claudin-5 expression at a concentration of 7.5 g/ml. In contrast, P. aeruginosa LPS decreased (P < 0.05) claudin-5 expression only at the highest concentration tested (i.e., 30 g/ml). Coadministration of therapeutic concentrations of colistin ameliorated the S. enterica LPS-induced reduction in claudin-5 expression in hCMEC/D3 cells and the perturbation in BBB function in mice. This study demonstrates that BBB disruption induced by LPS is species dependent, at least between P. aeruginosa and S. enterica, and can be ameliorated by colistin.T he blood-brain barrier (BBB) is formed by specialized endothelial cells of cerebral microvessels. Unlike endothelial cells in other organs, the layer of endothelial cells lining the cerebral microvessels constitutes a physical barrier between blood and brain tissue by a complex network of tight junctions (TJs) (1). The TJs consist of transmembrane proteins spanning the intercellular cleft; these proteins include occludin, claudins (particularly claudin-5) (2), and several cytoplasmic proteins, such as zonula occludens (3). Under normal conditions, these TJ proteins seal the paracellular route of the BBB, thus preventing the movement of relatively small hydrophilic molecules from the blood into the brain, ensuring homeostatic regulation of the central nervous system (CNS) (4).Alterations to TJ proteins and increases in BBB permeability are observed during various disease states, including peripheral hyperalgesia, bacterial meningitis, systemic inflammation, and sepsis (5-8). Indeed, we have demonstrated that systemic administration to mice of lipopolysaccharide (LPS), a key component of the outer membrane of Gram-negative bacteria, from Salmonella enterica (as a model of bacterium-induced inflammation) leads to BBB dysfunction (9). One proposed mechanism for the decreased paracellular integrity of the BBB in response to LPS involves elevated plasma c...

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“…A further example of a synthetic LPS derivative is a symmetric lipid A mimetic consisting of two glucose residues linked through a (6→6′) succinic diamide linker, with two sulfate groups in place of the phosphate moieties, which was found to bind MD‐2 and to compete successfully with toxic LPSs . This small number of examples represents the tip of the iceberg of the vast potential for therapeutic applications of compounds with antagonistic activity inspired by natural LPSs . In this context, the observation of very low or no immunostimulatory effects exerted by some LPSs isolated from several extremophile bacteria, in addition to the quasi‐infinite sources from which it is possible to isolate such microorganisms, constituted an indubitable incentive to intensify the research into LPS antagonist candidates.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Gram‐Negative Extremophile Lipopolysaccharides: Promising Source of Inspiration for a New Generation of Endotoxin Antagonists

et al. 2017

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Extremophiles are microorganisms exhibiting the fascinating capability to thrive in habitats that are considered clearly inhospitable. Extreme-loving microorganisms have acquired ever-increasing importance in the biomedical and pharmaceutical fields, with many of their bioactive products having long been used as life-saving drugs. In this context, extremophile Gram-negative bacterial lipopolysaccharides (LPSs) and their analogues offer many promising opportunities for a variety of biomedical and therapeutic applications. The structure-dependent capability to elicit and to modulate host immune responses is surely the most intriguing feature of LPSs in the context of new drug discovery and design. This review offers an overview of the chemical peculiarities of LPSs isolated from extremophile bacteria, providing the most promising results relating to their biological activity. We discuss the pharmacologically important potential of extremophile LPSs as fundamental immunomodulatory compounds from the perspective of drug synthesis and development

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Toll-like Receptor Activation of Human Cells by Synthetic Triacylated Lipid A-like Molecules

Cited by 16 publications

References 40 publications

TLR activation of tumor‐associated macrophages from ovarian cancer patients triggers cytolytic activity of NK cells

TLR activation of tumor‐associated macrophages from ovarian cancer patients triggers cytolytic activity of NK cells

Species-Dependent Blood-Brain Barrier Disruption of Lipopolysaccharide: Amelioration by ColistinIn VitroandIn Vivo

Gram‐Negative Extremophile Lipopolysaccharides: Promising Source of Inspiration for a New Generation of Endotoxin Antagonists

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