scholarly journals Toll-like Receptor 4 Modulation as a Strategy to Treat Sepsis

2010 ◽  
Vol 2010 ◽  
pp. 1-9 ◽  
Author(s):  
X. Wittebole ◽  
D. Castanares-Zapatero ◽  
P. F. Laterre
Keyword(s):  
Inflammatory Cytokine ◽  
Causes Of Death ◽  
Potential Role ◽  
Signalling Pathways ◽  
Gram Negative Bacteria ◽  
Toll Like Receptor ◽  
Tlr4 Expression ◽  
Toll Like Receptor 4 ◽  
Therapeutic Targeting ◽  
Sepsis And Septic Shock

Despite a decrease in mortality over the last decade, sepsis remains the tenth leading causes of death in western countries and one of the most common cause of death in intensive care units. The recent discovery of Toll-like receptors and their downstream signalling pathways allowed us to better understand the pathophysiology of sepsis-related disorders. Particular attention has been paid to Toll-like receptor 4, the receptor for Gram-negative bacteria outer membrane lipopolysaccharide or endotoxin. Since most of the clinical trial targeting single inflammatory cytokine in the treatment of sepsis failed, therapeutic targeting of Toll-like receptor 4, because of its central role, looks promising. The purpose of this paper is to focus on the recent data of various drugs targeting TLR4 expression and pathway and their potential role as adjunctive therapy in severe sepsis and septic shock.

scholarly journals Toll-Like Receptor 4 Reduces Oxidative Injury via Glutathione Activity in Sheep

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Shoulong Deng ◽  
Kun Yu ◽  
Qian Wu ◽  
Yan Li ◽  
Xiaosheng Zhang ◽  
...  
Keyword(s):  
Oxidative Injury ◽  
Innate Immune ◽  
Gram Negative Bacteria ◽  
Superoxide Dismutase 1 ◽  
Toll Like Receptor ◽  
Tlr4 Expression ◽  
Toll Like Receptor 4 ◽  
Transgenic Sheep ◽  
Glutamylcysteine Synthetase ◽  
Inflammatory Infiltrates

Toll-like receptor 4 (TLR4) is an important sensor of Gram-negative bacteria and can trigger activation of the innate immune system. Increased activation of TLR4 can lead to the induction of oxidative stress. Herein, the pathway whereby TLR4 affects antioxidant activity was studied. In TLR4-overexpressing sheep, TLR4 expression was found to be related to the integration copy number when monocytes were challenged with lipopolysaccharide (LPS). Consequently, production of malondialdehyde (MDA) was increased, which could increase the activation of prooxidative stress enzymes. Meanwhile, activation of an antioxidative enzyme, glutathione peroxidase (GSH-Px), was increased. Real-time PCR showed that expression of activating protein-1 (AP-1) and the antioxidative-related genes was increased. By contrast, the expression levels of superoxide dismutase 1 (SOD1) and catalase (CAT) were reduced. In transgenic sheep, glutathione (GSH) levels were dramatically reduced. Furthermore, transgenic sheep were intradermally injected with LPS in each ear. The amounts of inflammatory infiltrates were correlated with the number of TLR4 copies that were integrated in the genome. Additionally, the translation ofγ-glutamylcysteine synthetase (γ-GCS) was increased. Our findings indicated that overexpression of TLR4 in sheep could ameliorate oxidative injury through GSH secretion that was induced by LPS stimulation. Furthermore, TLR4 promotedγ-GCS translation through the AP-1 pathway, which was essential for GSH synthesis.

scholarly journals FTO (Fat-Mass and Obesity-Associated Protein) Participates in Hemorrhage-Induced Thalamic Pain by Stabilizing Toll-Like Receptor 4 Expression in Thalamic Neurons

Stroke ◽  
2021 ◽  
Author(s):  
Ganglan Fu ◽  
Shibin Du ◽  
Tianfeng Huang ◽  
Minghui Cao ◽  
Xiaozhou Feng ◽  
...  
Keyword(s):  
Fat Mass ◽  
Rna Binding ◽  
Intraperitoneal Administration ◽  
Toll Like Receptor ◽  
Tlr4 Expression ◽  
Toll Like Receptor 4 ◽  
Thalamic Neurons ◽  
Adeno Associated Virus ◽  
Meclofenamic Acid ◽  
Thalamic Pain

Background and Purpose: Hemorrhage-caused gene changes in the thalamus likely contribute to thalamic pain genesis. RNA N 6 -methyladenosine modification is an additional layer of gene regulation. Whether FTO (fat-mass and obesity-associated protein), an N 6 -methyladenosine demethylase, participates in hemorrhage-induced thalamic pain is unknown. Methods: Expression of Fto mRNA and protein was assessed in mouse thalamus after hemorrhage caused by microinjection of Coll IV (type IV collagenase) into unilateral thalamus. Effect of intraperitoneal administration of meclofenamic acid (a FTO inhibitor) or microinjection of adeno-associated virus 5 (AAV5) expressing Cre into the thalamus of Fto fl/fl mice on the Coll IV microinjection–induced TLR4 (Toll-like receptor 4) upregulation and nociceptive hypersensitivity was examined. Effect of thalamic microinjection of AAV5 expressing Fto (AAV5- Fto ) on basal thalamic TLR4 expression and nociceptive thresholds was also analyzed. Additionally, level of N 6 -methyladenosine in Tlr4 mRNA and its binding to FTO or YTHDF2 (YTH N 6 -methyladenosine RNA binding protein 2) were observed. Results: FTO was detected in neuronal nuclei of thalamus. Level of FTO protein, but not mRNA, was time-dependently increased in the ipsilateral thalamus on days 1 to 14 after Coll IV microinjection. Intraperitoneal injection of meclofenamic acid or adeno-associated virus-5 expressing Cre microinjection into Fto fl/fl mouse thalamus attenuated the Coll IV microinjection–induced TLR4 upregulation and tissue damage in the ipsilateral thalamus and development and maintenance of nociceptive hypersensitivities on the contralateral side. Thalamic microinjection of AAV5- Fto increased TLR4 expression and elicited hypersensitivities to mechanical, heat and cold stimuli. Mechanistically, Coll IV microinjection produced an increase in FTO binding to Tlr4 mRNA, an FTO-dependent loss of N 6 -methyladenosine sites in Tlr4 mRNA and a reduction in the binding of YTHDF2 to Tlr4 mRNA in the ipsilateral thalamus. Conclusions: Our findings suggest that FTO participates in hemorrhage-induced thalamic pain by stabilizing TLR4 upregulation in thalamic neurons. FTO may be a potential target for the treatment of this disorder.

scholarly journals ADAM17-Mediated Ectodomain Shedding of Toll-Like Receptor 4 as a Negative Feedback Regulation in Lipopolysaccharide-Activated Aortic Endothelial Cells

2018 ◽  
Vol 45 (5) ◽  
pp. 1851-1862 ◽  
Author(s):  
Won Seok Yang ◽  
Jin Ju Kim ◽  
Mee Jeong Lee ◽  
Eun Kyoung Lee ◽  
Su-Kil Park
Keyword(s):  
Endothelial Cells ◽  
P38 Mapk ◽  
Ectodomain Shedding ◽  
Toll Like Receptor ◽  
Tlr4 Expression ◽  
Toll Like Receptor 4 ◽  
Negative Feedback Regulation ◽  
Mapk Activation ◽  
Aortic Endothelial Cells ◽  
Aortic Endothelial

Background/Aims: Lipopolysaccharide (LPS)-activated monocytes/macrophages develop endotoxin tolerance in part by reducing cell surface toll-like receptor 4 (TLR4) through cluster of differentiation 14 (CD14)-dependent endocytosis. In case of endothelial cells, CD14 is expressed in low copy numbers as compared with monocytes/macrophages. Thus, we explored how endothelial cells regulate TLR4 expression after LPS stimulation. Methods: Cultured human aortic endothelial cells (HAECs) were treated with LPS. TLR4 expression was analyzed by Western blot analysis and immunofluorescence staining. A disintegrin and metalloprotease 17 (ADAM17) activity was measured using a fluorescent substrate. Results: TLR4 in cell lysate began to decrease within 30 min of LPS treatment with a maximal reduction at 2 h, and it was accompanied by an increase of N-terminal fragment of TLR4 in culture supernatant, indicating ectodomain shedding of the receptor. LPS activated p38 mitogen-activated protein kinase (p38 MAPK) and ADAM17, while LPS-induced ADAM17 activation was inhibited by SB203580, a p38 MAPK inhibitor. LPS-induced ectodomain shedding of TLR4 was attenuated by siRNA depletion of ADAM17 as well as TAPI-2 (an inhibitor of ADAM family) and SB203580. LPS pretreatment resulted in a blunted response of p38 MAPK activation to further LPS stimulation. In the cells depleted of ADAM17, LPS-induced p38 MAPK activation was prolonged and LPS-induced intercellular adhesion molecule-1 expression was potentiated. Conclusion: HAECs respond to LPS by rapid shedding of the ectodomain of TLR4 and thereby reduce the responsiveness to subsequent LPS exposure. ADAM17, downstream of p38 MAPK, is implicated in the ectodomain cleavage of TLR4.

scholarly journals Immunomodulatory Effects of Yersinia pestis Lipopolysaccharides on Human Macrophages

2009 ◽  
Vol 17 (1) ◽  
pp. 49-55 ◽  
Author(s):  
Motohiro Matsuura ◽  
Hideyuki Takahashi ◽  
Haruo Watanabe ◽  
Shinji Saito ◽  
Kazuyoshi Kawahara
Keyword(s):  
Inflammatory Response ◽  
Yersinia Pestis ◽  
Lipid A ◽  
Antagonistic Activity ◽  
Gram Negative Bacteria ◽  
Toll Like Receptor ◽  
Defense System ◽  
Toll Like Receptor 4 ◽  
Bacterial Binding ◽  
Binding Forms

ABSTRACTIn the current study, we investigated the activity of lipopolysaccharide (LPS) purified fromYersinia pestisgrown at either 27°C or 37°C (termed LPS-27 and LPS-37, respectively). LPS-27 containing hexa-acylated lipid A, similar to the LPS present in usual gram-negative bacteria, stimulated an inflammatory response in human U937 cells through Toll-like receptor 4 (TLR4). LPS-37, which did not contain hexa-acylated lipid A, exhibited strong antagonistic activity to the TLR4-mediated inflammatory response. The phagocytic activity in the cells was not affected by LPS-37. To estimate the activity of LPS in its bacterial binding form, formalin-killed bacteria (FKB) were prepared fromY. pestiscells grown at 27°C or 37°C (termed FKB-27 and FKB-37, respectively). FKB-27 strongly stimulated the inflammatory response. This activity was suppressed in the presence of an anti-TLR4 antibody but not an anti-TLR2 antibody. In addition, this activity was almost completely suppressed by LPS-37, indicating that the activity of FKB-27 is predominantly derived from the LPS-27 bacterial binding form. In contrast, FKB-37 showed no antagonistic activity. The results arising from the current study indicate thatY. pestiscauses infection in humans without stimulating the TLR4-based defense systemviabacterial binding of LPS-37, even when bacterial free LPS-37 is not released to suppress the defense system. This is in contrast to the findings for bacteria that possess agonistic LPS types, which are easily recognized by the defense systemviathe bacterial binding forms.

scholarly journals Toll-Like Receptor 4 (TLR4) Expression Affects Schwann Cell Behavior in vitro

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Huanhuan Zhang ◽  
Zhiwei Shao ◽  
Yun Zhu ◽  
Lingyu Shi ◽  
Zhihao Li ◽  
...  
Keyword(s):  
Schwann Cell ◽  
Cell Behavior ◽  
Toll Like Receptor ◽  
Tlr4 Expression ◽  
Toll Like Receptor 4

scholarly journals Downregulation of Lung Toll-Like Receptor 4 Could Effectively Attenuate Liver Transplantation-Induced Pulmonary Damage at the Early Stage of Reperfusion

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Xinjin Chi ◽  
Weifeng Yao ◽  
Ailan Zhang ◽  
Mian Ge ◽  
Jun Cai ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Polymorphonuclear Leukocytes ◽  
Early Stage ◽  
Pulmonary Inflammation ◽  
Toll Like Receptor ◽  
Tlr4 Expression ◽  
Toll Like Receptor 4 ◽  
Pulmonary Damage ◽  
Autologous Liver

Acute lung injury (ALI) is a severe complication of orthotopic liver transplantation (OLT) with unclear underline mechanism. Toll-like receptor 4 (TLR4) has been identified as a key receptor mediating inflammation. We hypothesized that TLR4-mediated pulmonary inflammation may contribute to development of ALI during OLT. Patients with or without ALI were observed for serum cytokines and expression of TLR4 on peripheral blood polymorphonuclear leukocytes (PMNs). Next, rats which underwent orthotopic autologous liver transplantation (OALT) were divided into sham and model groups. Pulmonary function and the level of TLR4 expression and cytokines were analyzed. Furthermore, the role of TLR4 in OALT-mediated ALI was assessed in rats treated with TLR4-siRNA before OALT. The PMNs TLR4 expression and the serum TNF-αand IL-βlevel were higher in patients with ALI than those with non-ALI. Interestingly, lung TLR4 expression was significantly increased after 8 hours of OALT with increased levels of TNF-αand IL-β, which lead to lung pathological damage and an increase of lung myeloperoxidase content. Moreover, knockdown of TLR4 reduced lung cytokines release and reversed the above pathologic changes after OALT and finally improved rats’ survival rate. In conclusion, TLR4 overexpression, potentially by stimulating proinflammatory cytokine overproduction, contributes to the development of ALI after OLT.

Statin treatment is associated with reduced toll-like receptor 4 immunohistochemical expression on carotid atherosclerotic plaques: a novel effect of statins

Vascular ◽  
2011 ◽  
Vol 19 (6) ◽  
pp. 320-326 ◽  
Author(s):  
Athanasios Katsargyris ◽  
Chris Klonaris ◽  
Sotirios Tsiodras ◽  
Elias Bastounis ◽  
Athanasios Giannopoulos ◽  
...  
Keyword(s):  
Carotid Plaque ◽  
Statin Treatment ◽  
Atherosclerotic Plaques ◽  
Toll Like Receptor ◽  
Tlr4 Expression ◽  
Immunohistochemical Expression ◽  
Toll Like Receptor 4 ◽  
Over Expression ◽  
Plaque Stabilization ◽  
Plaque Destabilization

Toll-like receptor 4 (TLR4) has been recently implicated in inflammatory pathways involved in carotid plaque destabilization. Given that statins have plaque stabilization and inflammation reduction effects, we investigated whether TLR4 expression on carotid atherosclerotic plaques correlates with statin intake. Carotid atherosclerotic plaques were obtained on 140 patients (preoperative statin intake, n = 70). TLR4 immunohistochemical expression was investigated in endothelial cells (ECs), macrophages (MACs) and smooth muscle cells (SMCs) of carotid atheroma. TLR4 positivity, over-expression and intensity of immunostaining were compared in statin versus no-statin users. The results of this study showed that statin users had a significantly lower expression of TLR4 in ECs ( P = 0.02, 0.001, 0.006 for TLR4 positivity, increased intensity and over-expression, respectively). Similarly, TLR4 positivity was less pronounced in carotid plaque MACs of statin users ( P = 0.03). No carotid specimen with increased EC TLR4 intensity or over-expression was observed among statin users. The prevalence of any cerebrovascular accident was 61.4% in the ‘no statin’ versus 18.6% in the ‘statin’ group (odds ratio for statin use: 0.14, 95% CI: 0.07–0.31, P < 0.001). In conclusion, statin treatment is associated with attenuated TLR4 expression on human carotid atherosclerotic plaques and a reduced risk of carotid-related cerebrovascular events. TLR4 may potentially mediate statins' plaque stabilization effects. Further investigation is necessary.

scholarly journals Effect of Spaceflight on Ability of Monocytes To Respond to Endotoxins of Gram-Negative Bacteria

2008 ◽  
Vol 15 (10) ◽  
pp. 1523-1528 ◽  
Author(s):  
Indreshpal Kaur ◽  
Elizabeth R. Simons ◽  
Asha S. Kapadia ◽  
C. Mark Ott ◽  
Duane L. Pierson
Keyword(s):  
Space Shuttle ◽  
Space Station ◽  
Gram Negative Bacteria ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Gram Negative ◽  
Time Points ◽  
Control Subjects ◽  
Intracellular Cytokines ◽  
Blood Specimens

ABSTRACT Astronauts live and work in relatively crowded, confined environments on the Space Shuttle and the International Space Station. They experience a unique set of stressors that contribute to a diminishment of many immune responses. This study investigated the ability of the shuttle crew members' monocytes to respond to gram-negative endotoxin that they could encounter during infections. Blood specimens were collected from 20 crew members and 15 control subjects 10 days before launch, 3 to 4 h after landing, and 15 days after landing and from crew members during their annual medical examination at 6 to 12 months after landing. When challenged with gram-negative endotoxin, the crew member's monocytes collected at all three time points produced lower levels of interleukin-6 (IL-6) and IL-1β and higher levels of IL-1ra and IL-8 compared to those of control subjects. Cytokines were assessed by measuring the number of cells positive for intracellular cytokines. These values returned to normal 6 to 12 months after landing, except for IL-1ra, which was still higher (five- to sixfold) than in controls. This phenomenon was accompanied by an increased expression of Toll-like receptor 4 and decreased expression of CD14 on the crew members' monocytes at all time points. There were also increased levels of the lipopolysaccharide binding protein in the plasma of the crew members 3 to 4 h and 15 days after landing. This study shows that spaceflight-associated factors (in-flight and preflight) modulate the response of monocytes to gram-negative endotoxins.

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