Molecular simplification of lipid A structure: TLR4-modulating cationic and anionic amphiphiles

Calabrese, Valentina; Cighetti, Roberto; Peri, Francesco

doi:10.1016/j.molimm.2014.05.011

Cited by 30 publications

(18 citation statements)

References 72 publications

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“…LPS, and especially its lipid A component, is highly lipophilic, and it therefore may be able to bind directly to plasma proteins, in an acute way. This might be one reason underlying the hypercoagulability [ 5 ], as well as a denser clot structure [ 53 , 54 ], as seen in various inflammatory diseases. Although we show here that exposure to even tiny amounts of LPS leads to an immediate (acute) change in the coagulability parameters, we recognize that this may happen simultaneously with chronic (longer-term) reactions ( figure 1 ).…”

Section: Discussionmentioning

confidence: 99%

Acute induction of anomalous and amyloidogenic blood clotting by molecular amplification of highly substoichiometric levels of bacterial lipopolysaccharide

Pretorius

Mbotwe

Bester

et al. 2016

J. R. Soc. Interface.

130

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It is well known that a variety of inflammatory diseases are accompanied by hypercoagulability, and a number of more-or-less longer-term signalling pathways have been shown to be involved. In recent work, we have suggested a direct and primary role for bacterial lipopolysaccharide (LPS) in this hypercoagulability, but it seems never to have been tested directly. Here, we show that the addition of tiny concentrations (0.2 ng l−1) of bacterial LPS to both whole blood and platelet-poor plasma of normal, healthy donors leads to marked changes in the nature of the fibrin fibres so formed, as observed by ultrastructural and fluorescence microscopy (the latter implying that the fibrin is actually in an amyloid β-sheet-rich form that on stoichiometric grounds must occur autocatalytically). They resemble those seen in a number of inflammatory (and also amyloid) diseases, consistent with an involvement of LPS in their aetiology. These changes are mirrored by changes in their viscoelastic properties as measured by thromboelastography. As the terminal stages of coagulation involve the polymerization of fibrinogen into fibrin fibres, we tested whether LPS would bind to fibrinogen directly. We demonstrated this using isothermal calorimetry. Finally, we show that these changes in fibre structure are mirrored when the experiment is done simply with purified fibrinogen and thrombin (±0.2 ng l−1 LPS). This ratio of concentrations of LPS : fibrinogen in vivo represents a molecular amplification by the LPS of more than 108-fold, a number that is probably unparalleled in biology. The observation of a direct effect of such highly substoichiometric amounts of LPS on both fibrinogen and coagulation can account for the role of very small numbers of dormant bacteria in disease progression in a great many inflammatory conditions, and opens up this process to further mechanistic analysis and possible treatment.

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Section: Discussionmentioning

confidence: 99%

Acute induction of anomalous and amyloidogenic blood clotting by molecular amplification of highly substoichiometric levels of bacterial lipopolysaccharide

Pretorius

Mbotwe

Bester

et al. 2016

J. R. Soc. Interface.

130

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“…The bacterial endotoxin LPS (lipopolysaccharide) is the natural TLR4-activating ligand but other activating ligands were also described, including endogenous danger-associated molecular patterns released as a consequence of injury and inflammation, such as heat-shock proteins, extracellular matrix molecules (hyaluronan), HMGB1, oxidized low-density lipoprotein and oxidized phospholipids. 62 , 63 , 64 These are unlikely to be involved in our system, because the PKA/pCREB/TH signal was not seen in WT animals, which are also likely to be LPS+, and all the groups were free of overt injury/inflammation. However, we do not exclude the possible involvement of recently identified agonists, such as saturated fatty acids, LPS mimetic ligands of natural origin, including polypeptides and neuron-derived IgG in dopaminergic neurons.…”

Section: Discussionmentioning

confidence: 99%

TLR4 signaling in VTA dopaminergic neurons regulates impulsivity through tyrosine hydroxylase modulation

et al. 2016

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Alcohol dependence is a complex disorder that initiates with episodes of excessive alcohol drinking known as binge drinking, and has a 50–60% risk contribution from inherited susceptibility genes. Cognitive impulsivity is a heritable trait that may set the stage for transition to alcohol dependence but its role in the ethanol-seeking behavior and the involved genes are still poorly understood. We have previously shown that alcohol-preferring P rats have innately elevated levels of a neuronal Toll-like receptor 4 (TLR4) signal in the ventral tegmental area (VTA) that controls the initiation of excessive alcohol drinking. Here we report that TLR4 is localized in dopaminergic (TH+) neurons and it upregulates the expression of tyrosine hydroxylase (TH) through a cAMP-dependent protein kinase (PKA)/cyclic AMP response element binding protein (CREB) signal. P rats have higher impulsivity than wild-type (WT) rats and VTA infusion of a non-replicating Herpes simplex virus (HSV) vector for TLR4-specific small interfering RNA (siRNA; pHSVsiTLR4) inhibits both impulsivity and TLR4/TH expression. A scrambled siRNA vector does not affect gene expression or impulsivity. The data suggest that TLR4 signaling in VTA dopaminergic neurons controls impulsivity related to the regulation of TH expression, likely contributing to the initiation of alcohol drinking and its transition to alcohol dependence.

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“…LPS, and especially its lipid A component, is highly lipophilic, and it therefore may be able to bind directly to plasma proteins, in an acute way. This might be one reason underlying the hypercoagulability [5], as well as a denser clot structure [52,53], as seen in various inflammatory diseases. Although we show here that exposure to even tiny amounts of LPS leads to an immediate (acute) change in the coagulability parameters, we recognize that this may happen simultaneously with the chronic (longer-term) reactions (Fig 1).…”

Section: Discussionmentioning

confidence: 99%

Acute induction of anomalous blood clotting by molecular amplification of highly substoichiometric levels of bacterial lipopolysaccharide (LPS)

Pretorius

Bester²,

Mbotwa

et al. 2016

Preprint

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Significance statement (120 words)Most chronic diseases (including those classified as cardiovascular, neurodegenerative, or autoimmune) are accompanied by long-term inflammation. Although typically mediated by 'inflammatory' cytokines, the origin of this inflammation is unclear. We have suggested that one explanation is a dormant microbiome that can shed the highly inflammatory lipopolysaccharide LPS. Such inflammatory diseases are also accompanied by a hypercoagulable phenotype. We here show directly (using 6 different methods) that very low concentrations of LPS can affect the terminal stages of the coagulation properties of blood and plasma significantly, and that this may be mediated via a direct binding of LPS to a small fraction of fibrinogen monomers as assessed biophysically. Such amplification methods may be of more general significance. BY 4.0 International license not peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was . http:

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Molecular simplification of lipid A structure: TLR4-modulating cationic and anionic amphiphiles

Cited by 30 publications

References 72 publications

Acute induction of anomalous and amyloidogenic blood clotting by molecular amplification of highly substoichiometric levels of bacterial lipopolysaccharide

Acute induction of anomalous and amyloidogenic blood clotting by molecular amplification of highly substoichiometric levels of bacterial lipopolysaccharide

TLR4 signaling in VTA dopaminergic neurons regulates impulsivity through tyrosine hydroxylase modulation

Acute induction of anomalous blood clotting by molecular amplification of highly substoichiometric levels of bacterial lipopolysaccharide (LPS)

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