scholarly journals Central Role of Toll-Like Receptor 4 Signaling and Host Defense in Experimental Pneumonia Caused by Gram-Negative Bacteria

2005 ◽  
Vol 73 (1) ◽  
pp. 532-545 ◽  
Author(s):  
Jill R. Schurr ◽  
Erana Young ◽  
Pat Byrne ◽  
Chad Steele ◽  
Judd E. Shellito ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adaptor Protein ◽  
Mouse Strains ◽  
Gram Negative Bacteria ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Tlr4 Signaling ◽  
Gram Negative ◽  
Experimental Pneumonia

ABSTRACT Toll-like receptor 4 (TLR4) has been identified as a receptor for lipopolysaccharide. However, the precise role of TLR4 in regulating gene expression in response to an infection caused by gram-negative bacteria has not been fully elucidated. The role of TLR4 signaling in coordinating gene expression was assessed by gene expression profiling in lung tissue in a mouse model of experimental pneumonia with a low-dose infection of Klebsiella pneumoniae. We analyzed four mouse strains: C57BL/6 mice, which are resistant to bacterial dissemination; 129/SvJ mice, which are susceptible; C3H/HeJ mice, which are susceptible and have defective TLR4 signaling; and their respective control strain, C3H/HeN (intermediate resistance). At 4 h after infection, C57BL/6 and C3H/HeN mice demonstrated the greatest number of genes, with 67 shared induced genes which were TLR4 dependent and highly associated with the resistance phenotype. These genes included cytokine and chemokine genes required for neutrophil activation or recruitment, growth factor receptors, MyD88 (a critical adaptor protein for TLR signaling), and adhesion molecules. TLR4 signaling accounted for over 74% of the gene expression in the C3H background. These data suggest that early TLR4 signaling controls the vast majority of gene expression in the lung in response to an infection caused by gram-negative bacteria and that this subsequent gene expression determines survival of the host.

scholarly journals Toll-Like Receptor 4 Protects Against Clostridium perfringens Infection in Mice

2021 ◽  
Vol 11 ◽  
Author(s):  
Masaya Takehara ◽  
Keiko Kobayashi ◽  
Masahiro Nagahama
Keyword(s):  
Clostridium Perfringens ◽  
Gram Negative Bacteria ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Gram Positive ◽  
Gram Negative ◽  
Tlr4 Agonist ◽  
Innate Ability ◽  
Recognition Receptor

Toll-like receptor 4 (TLR4) has been reported to protect against Gram-negative bacteria by acting as a pathogen recognition receptor that senses mainly lipopolysaccharide (LPS) from Gram-negative bacteria. However, the role of TLR4 in Gram-positive bacterial infection is less well understood. Clostridium perfringens type A is a Gram-positive bacterium that causes gas gangrene characterized by severe myonecrosis. It was previously demonstrated that C. perfringens θ-toxin is a TLR4 agonist, but the role of TLR4 in C. perfringens infection is unclear. Here, TLR4-defective C3H/HeJ mice infected with C. perfringens showed a remarkable decrease in survival rate, an increase in viable bacterial counts, and accelerated destruction of myofibrils at the infection site compared with wild-type C3H/HeN mice. These results demonstrate that TLR4 plays an important role in the elimination of C. perfringens. Remarkable increases in levels of inflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and granulocyte colony-stimulating factor (G-CSF), were observed in C. perfringens-infected C3H/HeN mice, whereas the increases were limited in C3H/HeJ mice. Generally, increased G-CSF accelerates granulopoiesis in the bone marrow and the spleen to exacerbate neutrophil production, resulting in elimination of bacteria. The number of neutrophils in the spleen was increased in C. perfringens-infected C3H/HeN mice compared with non-infected mice, while the increase was lower in C. perfringens-infected C3H/HeJ mice. Furthermore, DNA microarray analysis revealed that the mutation in TLR4 partially affects host gene expression during C. perfringens infection. Together, our results illustrate that TLR4 is crucial for the innate ability to eliminate C. perfringens.

scholarly journals Toll-Like Receptor 4 Signaling and Drug Addiction

2020 ◽  
Vol 11 ◽  
Author(s):  
Ruyan Wu ◽  
Jun-Xu Li
Keyword(s):  
Drug Addiction ◽  
Multiple Drug ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Tlr4 Signaling ◽  
Drug Classes ◽  
Downstream Effectors ◽  
Potential Efficacy ◽  
Proinflammatory Responses

The emphasis of neuronal alterations and adaptations have long been the main focus of the studies of the mechanistic underpinnings of drug addiction. Recent studies have begun to appreciate the role of innate immune system, especially toll-like receptor 4 (TLR4) signaling in drug reward-associated behaviors and physiology. Drugs like opioids, alcohol and psychostimulants activate TLR4 signaling and subsequently induce proinflammatory responses, which in turn contributes to the development of drug addiction. Inhibition of TLR4 or its downstream effectors attenuated the reinforcing effects of opioids, alcohol and psychostimulants, and this effect is also involved in the withdrawal and relapse-like behaviors of different drug classes. However, conflicting results also argue that TLR4-related immune response may play a minimal part in drug addiction. This review discussed the preclinical evidence that whether TLR4 signaling is involved in multiple drug classes action and the possible mechanisms underlying this effect. Moreover, clinical studies which examined the potential efficacy of immune-base pharmacotherapies in treating drug addiction are also discussed.

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.

scholarly journals Toll-like receptor 4 is not required for the full maturation of dendritic cells or for the degradation of Gram-negative bacteria

2002 ◽  
Vol 32 (10) ◽  
pp. 2800-2806 ◽  
Author(s):  
Maria Rescigno ◽  
Matteo Urbano ◽  
Monica Rimoldi ◽  
Barbara Valzasina ◽  
Gianluca Rotta ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Gram Negative Bacteria ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Gram Negative

Increased Expressions of Toll-Like Receptor 4 on Platelet Are Related to Type of Bacteria and Disease Severity in Patients with Sepsis

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5365-5365
Author(s):  
Liping Ma ◽  
Xiu-Ju Wang ◽  
Da-Nian Nie ◽  
Yi-Qing Li ◽  
Shuang-Fen Xie ◽  
...  
Keyword(s):  
Blood Platelets ◽  
Inflammatory Cells ◽  
Gram Negative Bacteria ◽  
Toll Like Receptor ◽  
Microbial Infection ◽  
Toll Like Receptor 4 ◽  
Gram Positive ◽  
Severe Problem ◽  
Gram Negative ◽  
Gram Positive Bacteria

Abstract Early diagnosis and treatment of patients with sepsis remain a common and severe problem, especially in leukopenic patients.. Toll-like receptor-4 (TLR4) plays a crucial role in immunity as the first defenses system against microbial infection through binding gram-negative bacterial LPS. Blood platelets are not only involved in hemostasis, they also have many features of classic inflammatory cells. The expression of TLR4 on platelet in patients with sepsis, including gram-positive bacteria and gram-negative bacteria, is not known. Studying the differences between them, we investigated whether the expressions of TLR4 on platelet were associated with platelet activation, serum TNF-a and endotoxin levels in patients with sepsis, 8 patients of them with gram-positive bacteria and 15 patients of them with gram-negative bacteria. The number of platelet and function of coagulation were normal before infecting. Comparing with the heath subjects, the expressions of TLR4 and P-selectin on platelets, the levels of serum TNF-a and endotoxin were higher (P<0.05),and there was a positive correlation was observed between TLR4 and P-selectin, TNF-a, endotoxin respectively, among the gram-negative bacterial subjects. The phenomena were not found among the gram-positive bacterial subjects. In addition, among the gram-negative bacterial subjects, the expression of TLR4 was higher in patients with decreased number of platelets than with normal number of platelets. These results suggest that increased TLR4 on platelet might be an important early sign of gram-negative bacteria in patient with sepsis, it contributes to platelet activating, the inflammatory process and disease activity in infecting host. Above has be doing in more patients with positive blood bacteria culture in our Lab.

scholarly journals Toll-Like Receptor 4 Promotes NO Synthesis by Upregulating GCHI Expression under Oxidative Stress Conditions in Sheep Monocytes/Macrophages

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Shoulong Deng ◽  
Kun Yu ◽  
Baolu Zhang ◽  
Yuchang Yao ◽  
Zhixian Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Inflammatory Responses ◽  
Gram Negative Bacteria ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Gram Negative ◽  
Transgenic Sheep ◽  
And Oxidative Stress

Many groups of Gram-negative bacteria cause diseases that are harmful to sheep. Toll-like receptor 4 (TLR4), which is critical for detecting Gram-negative bacteria by the innate immune system, is activated by lipopolysaccharide (LPS) to initiate inflammatory responses and oxidative stress. Oxidation intermediates are essential activators of oxidative stress, as low levels of free radicals form a stressful oxidative environment that can clear invading pathogens. NO is an oxidation intermediate and its generation is regulated by nitric oxide synthase (iNOS). Guanosine triphosphate cyclohydrolase (GCHI) is the rate-limiting enzyme for tetrahydrobiopterin (BH4) synthesis, which is essential for the production of inducible iNOS. Previously, we made vectors to overexpress the sheepTLR4gene. Herein, first generation (G1) of transgenic sheep was stimulated with LPSin vivoandin vitro, and oxidative stress and GCHI expression were investigated. Oxidative injury caused by TLR4 overexpression was tightly regulated in tissues. However, the transgenic (Tg) group still secreted nitric oxide (NO) when an iNOS inhibitor was added. Furthermore, GCHI expression remained upregulated in both serum and monocytes/macrophages. Thus, overexpression of TLR4 in transgenic sheep might accelerate the clearance of invading microbes through NO generation following LPS stimulation. Additionally, TLR4 overexpression also enhances GCHI activation.

scholarly journals Role ofToll-Like Receptor 4 in Gram-Positive and Gram-Negative Pneumonia inMice

2004 ◽  
Vol 72 (2) ◽  
pp. 788-794 ◽  
Author(s):  
Judith Branger ◽  
Sylvia Knapp ◽  
Sebastiaan Weijer ◽  
Jaklien C. Leemans ◽  
Jennie M. Pater ◽  
...  
Keyword(s):  
Immune Response ◽  
Mutant Mice ◽  
Respiratory Pathogen ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Gram Positive ◽  
Gram Negative ◽  
High Level ◽  
Bacterial Outgrowth

ABSTRACT To determine the role of Toll-like receptor 4 (TLR4) in the immune response to pneumonia, C3H/HeJ mice (which display a mutant nonfunctional TLR4) and C3H/HeN wild-type mice were intranasally infected with either Streptococcus pneumoniae (a common gram-positive respiratory pathogen) or Klebsiella pneumoniae (a common gram-negative respiratory pathogen). In cases of pneumococcal pneumonia, TLR4 mutant mice showed a reduced survival only after infection with low-level bacterial doses, which was associated with a higher bacterial burden in their lungs 48 h postinfection. In Klebsiella pneumonia, TLR4 mutant mice demonstrated a shortened survival after infection with either a low- or a high-level bacterial dose together with an enhanced bacterial outgrowth in their lungs. These data suggest that TLR4 contributes to a protective immune response in both pneumococcal and Klebsiella pneumonia and that its role is more important in respiratory tract infection caused by the latter (gram-negative) pathogen.

scholarly journals Phagocytosis and intracellular killing of MD-2 opsonized Gram-negative bacteria depend on TLR4 signaling

Blood ◽  
2008 ◽  
Vol 111 (9) ◽  
pp. 4637-4645 ◽  
Author(s):  
Vishal Jain ◽  
Annett Halle ◽  
Kristen A. Halmen ◽  
Egil Lien ◽  
Marie Charrel-Dennis ◽  
...  
Keyword(s):  
Mutant Form ◽  
Gram Negative Bacteria ◽  
Dependent Manner ◽  
Intracellular Killing ◽  
Toll Like Receptor 4 ◽  
Cellular Activation ◽  
Gram Negative ◽  
Signaling Axis ◽  
Deficient Mice

AbstractBoth Toll-like receptor 4 (TLR4)– and MD-2–deficient mice succumb to otherwise nonfatal Gram-negative bacteria inocula, demonstrating the pivotal role played by these proteins in antibacterial defense in mammals. MD-2 is a soluble endogenous ligand for TLR4 and a receptor for lipopolysaccharide (LPS). LPS-bound MD-2 transmits an activating signal onto TLR4. In this report, we show that both recombinant and endogenous soluble MD-2 bind tightly to the surface of live Gram-negative bacteria. As a consequence, MD-2 enhances cellular activation, bacterial internalization, and intracellular killing, all in a TLR4-dependent manner. The enhanced internalization of MD-2–coated bacteria was not observed in macrophages expressing Lpsd, a signaling-incompetent mutant form of TLR4, suggesting that the enhanced phagocytosis observed is dependent on signal transduction. The data confirm the notion that soluble MD-2 is a genuine opsonin that enhances proinflammatory opsonophagocytosis by bridging live Gram-negative bacteria to the LPS transducing complex. The presented results extend our understanding of the role of the TLR4/MD-2 signaling axis in bacterial recognition by phagocytes.

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