Toll-Like Receptors -2, -3, -4 and -7 Expression Patterns in the Liver of a CLP-Induced Sepsis Mouse Model (original) (raw)
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Expression of Toll-like receptors (TLRs) in the lungs of an experimental sepsis mouse model
PloS one, 2017
Sepsis is a condition characterized by high mortality rates and often accompanied by multiple-organ dysfunction. During sepsis, respiratory system may be affected and possibly result in acute respiratory distress syndrome (ARDS). Toll-like receptors (TLRs), as a first line defense against invading pathogens, seem to be highly expressed in septic states. Therefore, expression of TLRs in the lungs of a sepsis animal model could indicate the involvement of the respiratory system and appear as a severity index of the clinical course. A total of 72 C57BL/6J mice, aged 12-14 weeks, were studied. The animals were divided into 3 sepsis (S) groups (24h, 48h and 72h) and 3 control (C) groups (24h, 48h and 72h), each consisting of 12 mice. The S-groups were subjected to cecal ligation and puncture (CLP) while the C-groups had a sham operation performed. Blood samples were drawn from all groups. Total blood count analysis was performed along with the measurement of certain biochemical markers. ...
Scientific Reports
Toll-like receptors (TLRs) are the key regulators of innate and adaptive immunity and are highly expressed during sepsis. Thus, studying the expression of TLRs in an animal septic model might indicate their possible association with acute kidney injury in sepsis. Seventy-two male C57BL/6J mice were used for this study. Randomly, these animals were divided into 6 groups (N = 12/group): 3 control and 3 septic groups depending on the euthanasia time (24 h, 48 h, 72 h). Septic groups underwent cecal ligation and puncture (CLP) to induce peritonitis, while control groups had a sham operation. Hematological tests were performed in serum for immune biomarkers; immunohistochemistry, morphometry and qRT-PCR analysis were used on both kidney and intestine tissues to evaluate the expression of TLR 2, 3, 4 and 7 in a septic process. At the end of each experimental period, we found that TLRs 2, 3, 4 and 7 were expressed in both tissues but there were differences between those at various time points. Also, we found that mRNA levels were significantly higher in qRT-PCR evaluation in septic groups than control groups in both kidney and intestinal tissues (p < 0.05); showing a steady increase in the septic groups as the time to euthanasia was prolonged (p < 0.05). Overall, our study provides a suggestion that TLRs 2, 3, 4 and 7 are highly expressed in the kidneys of septic mice and especially that these TLRs are sensitive and specific markers for sepsis. Finally, our study supports the diagnostic importance of TLRs in AKI and provides an insight on the contribution of septic mice models in the study of multi organ dysfunction syndrome in general.
Severe sepsis and Toll-like receptors
Seminars in Immunopathology, 2008
Severe sepsis dominates the mortality of noncardiac intensive care units. The ingenious Toll-like receptor (TLR) system can recognise many infectious organisms through relatively few receptors to trigger pro-inflammatory and anti-inflammatory cytokine release. Further complexity arises from positive and negative signalling feedback loops.
Immunology, 2003
Genetically determined responsiveness to microbial stimuli such as lipopolysaccharide (LPS) may affect the pathophysiology of human sepsis. The D299G mutation in human Toll-like receptor-4 (TLR4) impairs LPS signalling in homozygous and heterozygous individuals. To investigate whether the presence of the TLR4(D299G) mutation may correlate with the development or outcome of sepsis following major visceral surgery the presence of TLR4(D299G) mutation was analysed in 307 Caucasian patients (154 without and 153 with sepsis). Sepsis was caused in 84% of patients by polymicrobial infection. The presence of the mutant TLR4 did not signi®cantly correlate with development or outcome of sepsis. Serum levels of tumour necrosis factor, interleukin (IL)-10, and IL-6 at sepsis onset did not signi®cantly differ between patients carrying wild-type and mutant TLR4. Moreover, studies in a murine model of polymicrobial septic peritonitis demonstrated that TLR4-de®ciency did neither in¯uence the systemic cytokine response nor the development of organ injury. The results suggest that the signalling capacity of TLR4 as affected by loss-offunction mutations does not in¯uence human or experimental sepsis caused by polymicrobial infection. Thus, in polymicrobial infection, other innate immune receptors may compensate for TLR4 defects.
Toll-Like Receptors 2 and 4 Contribute to Sepsis-Induced Depletion of Spleen Dendritic Cells
Infection and Immunity, 2009
Depletion of dendritic cells (DC) in secondary lymphoid organs is a hallmark of sepsis-induced immune dysfunction. In this setting, we investigated if Toll-like receptor (TLR)-dependent signaling might modulate the maturation process and the survival of DC. Using a model of sublethal polymicrobial sepsis induced by cecal ligation and puncture, we investigated the quantitative and functional features of spleen DC in wild-type, TLR2 −/− , TLR4 −/− , and TLR2 −/− TLR4 −/− mice. By 24 h, a decrease in the relative percentage of CD11c high spleen DC occurred in wild-type mice but was prevented in TLR2 −/− , TLR4 −/− , and TLR2 −/− TLR4 −/− mice. In wild-type mice, sepsis dramatically affected both CD11c + CD8α + and CD11c + CD8α − subsets. In all three types of knockout mice studied, the CD11c + CD8α + subset followed a depletion pattern similar to that for wild-type mice. In contrast, the loss of CD11c + CD8α − cells was attenuated in TLR2 −/− and TLR4 −/− mice and completely prevented ...
Inflammation Research, 2010
Objective The role of Toll-like receptor 7 (TLR7), so far regarded as a receptor for viral RNA, was evaluated in a murine sepsis model. Material We used the colon ascendens stent peritonitis model (CASP) in female C57B/6 mice. R-848 (1.5 lg/g body weight) was injected intravenously prior to sepsis induction. Methods We determined levels of cytokines by CBA detection kit. Different cell populations were isolated from the spleen by magnetic cell separation and the expression of TLR7 was visualized by immunofluorescence staining. Bacterial load of organs was quantified by incubating suspensions on agar in colony forming units. Results R-848 application per se led to elevated cytokine levels in serum, spleen and peritoneal cavity. Expression of TLR7 on splenocytes was upregulated following CASP. Bacterial clearance in polymicrobial sepsis was significantly increased in spleen and peritoneum of mice pretreated with the TLR7-agonist. Cytokine release was regulated in the peritoneum and spleen. Furthermore, apoptosis in thymus and spleen during polymicrobial sepsis was significantly decreased following TLR7 agonist application. Conclusions TLR7 seems to be essential for pathogen defence not only in viral but also in bacterial infections. Pharmacological stimulation of this receptor prior to induction of sepsis improves the host's capacity to cope with pathogens.
Injury, sepsis, and the regulation of Toll-like receptor responses
Journal of Leukocyte Biology, 2003
Although we tend to think that the immune system has evolved to protect the host from invading pathogens and to discriminate between self and nonself, there must also be an element of the immune system that has evolved to control the response to tissue injury. Moreover, these potential immune-regulatory pathways controlling the injury response have likely coevolved in concert with self and nonself discriminatory immune-regulatory networks with a similar level of complexity. From a clinical perspective, severe injury upsets normal immune function and can predispose the injured patient to developing lifethreatening infectious complications. This remains a significant health care problem that has driven decades of basic and clinical research aimed at defining the functional effects of injury on the immune system. This review and update on our ongoing research efforts addressing the immunological response to injury will highlight some of the most recent advances in our understanding of the impact that severe injury has on the innate-and adaptive-immune system focusing on phenotypic changes in innate-immune cell responses to Tolllike receptor stimulation.
TLR4 influences the humoral and cellular immune response during polymicrobial sepsis
Injury, 2010
Sepsis, systemic inflammatory response syndrome (SIRS) and associated multiple organ failure (MOF) as well as the multiple organ dysfunction syndrome (MODS) remain the most common causes for fatalities during the clinical course following trauma or major surgery. Both the innate and the adaptive immune systems are activated and contribute to a complex pathogenesis of sepsis. As part of the innate immune system, Toll-like receptors (TLRs) play a central role in the early immune response during sepsis. In contrast to the adaptive immune system, TLRs react rapidly on a wide range of pathogen-associated molecular patterns (PAMPs) 1 without prior exposure. They are activated not only by PAMPs but also by dangerassociated molecular patterns (DAMPs). 1,38 TLRs build the initial line of host defence in the human organism and the 13 TLRs identified to date 47 are expressed on many immune cells such as polymorpho-nuclear granulocytes (PMN), macrophages, dendritic cells and certain epithelial cells. These immune cells recruit further leucocytes through cytokine production to fight the invading micro-organism. The most famous member of the TLR-family, TLR4, is activated by lipopolysaccharide (LPS), a component of the membrane of Gram-negative bacteria. Once activated, production of proinflammatory cytokines such as tumour necrosis factor-a (TNFa), interleukin (IL)-1b or IL-6 40 is induced through an intracellular signalling cascade. 35 These pro-inflammatory mediators are released into the peripheral blood and lead to activation and extravasation of T-cells, macrophages and PMNs. The release of these inflammatory mediators correlates with the clinical entity of SIRS or septic shock. Lymphocyte sub-populations such as CD4 + , CD8 + and CD56 + natural killer (NK) cells show a strong influence on the course of sepsis. A decreased CD4 + /CD8 + ratio was associated with a lower incidence of MODS. 26 Furthermore, an increase of NK cells was associated with increased mortality after caecal ligation and puncture (CLP) in dehydroepiandrosterone (DHEA)-treated mice, 41 while depletion of NK cells showed a beneficial effect. 7 Injury, Int.
Journal of Interferon & Cytokine Research, 2000
Toll-like receptor (TLR) 2 and TLR4 are members of the interleukin-1 receptor (IL-1R) family and transduce similar signals as IL-1R in response to bacteria and bacterial components. In this study, we investigated the regulation of their gene expression in murine tissues, especially in the liver and hepatocytes. When mice were administered lipopolysaccharide (LPS), TLR2 mRNA was upregulated in the brain, heart, lung, liver, and kidney. In contrast, it was downregulated in the spleen. TLR4 mRNA was decreased in the brain. In the heart and lung, it increased, and it was not affected in the liver, kidney, and spleen. TLR mRNA was further analyzed in the liver and hepatocytes. Like LPS treatment, administration of IL-1, IL-6, or tumor necrosis factor (TNF) upregulated TLR2 mRNA. However, none of them affected the TLR4 mRNA level. In primary cultured hepatocytes, TLR2 mRNA was upregulated by LPS, IL-1, or TNF but not by IL-6 or dexamethasone. None of them affected TLR4 mRNA expression. Similar responses were observed in the murine hepatoma cell line Hepa 1-6. These results suggest that in infection with gram-negative bacteria, LPS and proinflammatory cytokines differentially regulate gene expression of TLR2 and TLR4 in murine hepatocytes, which may lead to pathologic and host defense reactions in the liver. 915 Recent studies revealed that TLR2 recognizes various bacteria and cell wall components, such as whole gram-positive bacteria and their peptidoglycan and lipoteichoic acid (LTA), and lipoprotein/lipopeptides from mycobacteria, Borrelia burgdorferi, and mycoplasma, and mycobacterial lipoarabinomannan. In contrast, TLR4 recognizes LPS. Heat shock protein 60 (hsp60) is also able to bind TLR4. Thus, it may be an endogenous ligand. (46) Although TLR2 was initially reported to function as a signal transducer for LPS, this receptor does not seem to be the main transducer of LPS signaling because TLR2-deficient mice respond to LPS to the same extent as do wild-type mice.