104 research outputs found
Toll-like receptor 2 contributes to antibacterial defence against pneumolysin-deficient pneumococci
No full text© 2008 Blackwell Publishing LtdToll-like receptors (TLRs) are pattern recognition receptors that recognize conserved molecular patterns expressed by pathogens. Pneumolysin, an intracellular toxin found in all Streptococcus pneumoniae clinical isolates, is an important virulence factor of the pneumococcus that is recognized by TLR4. Although TLR2 is considered the most important receptor for Gram-positive bacteria, our laboratory previously could not demonstrate a decisive role for TLR2 in host defence against pneumonia caused by a serotype 3 S. pneumoniae. Here we tested the hypothesis that in the absence of TLR2, S. pneumoniae can still be sensed by the immune system through an interaction between pneumolysin and TLR4. C57BL/6 wild-type (WT) and TLR2 knockout (KO) mice were intranasally infected with either WT S. pneumoniae D39 (serotype 2) or the isogenic pneumolysin-deficient S. pneumoniae strain D39 PLN. TLR2 did not contribute to antibacterial defence against WT S. pneumoniae D39. In contrast, pneumolysin-deficient S. pneumoniae only grew in lungs of TLR2 KO mice. TLR2 KO mice displayed a strongly reduced early inflammatory response in their lungs during pneumonia caused by both pneumolysin-producing and pneumolysin-deficient pneumococci. These data suggest that pneumolysin-induced TLR4 signalling can compensate for TLR2 deficiency during respiratory tract infection with S. pneumoniae.Mark C. Dessing, Sandrine Florquin, James C. Paton and Tom van der Pol
TREM1/3 deficiency impairs tissue repair after acute kidney injury and mitochondrial metabolic flexibility in tubular epithelial cells
No full textLong-term sequelae of acute kidney injury (AKI) are associated with incomplete recovery of renal function and the development of chronic kidney disease (CKD), which can be mediated by aberrant innate immune activation, mitochondrial pathology, and accumulation of senescent tubular epithelial cells (TECs). Herein, we show that the innate immune receptor Triggering receptor expressed on myeloid cells-1 (TREM-1) links mitochondrial metabolism to tubular epithelial senescence. TREM-1 is expressed by inflammatory and epithelial cells, both players in renal repair after ischemia/reperfusion (IR)-induced AKI. Hence, we subjected WT and TREM1/3 KO mice to different models of renal IR. TREM1/3 KO mice displayed no major differences during the acute phase of injury, but increased mortality was observed in the recovery phase. This detrimental effect was associated with maladaptive repair, characterized by persistent tubular damage, inflammation, fibrosis, and TEC senescence. In vitro, we observed an altered mitochondrial homeostasis and cellular metabolism in TREM1/3 KO primary TECs. This was associated with G2/M arrest and increased ROS accumulation. Further exposure of cells to ROS-generating triggers drove the cells into a stress-induced senescent state, resulting in decreased wound healing capacity. Treatment with a mitochondria anti-oxidant partly prevented the senescent phenotype, suggesting a role for mitochondria herein. In summary, we have unraveled a novel (metabolic) mechanism by which TREM1/3 deficiency drives senescence in TECs. This involves redox imbalance, mitochondrial dysfunction and a decline in cellular metabolic activities. These finding suggest a novel role for TREM-1 in maintaining tubular homeostasis through regulation of mitochondrial metabolic flexibility
Immune-mediated mechanisms of (mal)adaptive renal tissue repair
No full textThe aim of this thesis is to increase our knowledge into the immunopathogenesis of renal sterile inflammatory diseases, with a focus on the innate immune response activation by the danger protein S100A8/A9 and the receptor TREM-1. We found that S100A8/A9 is a pivotal player in renal repair following hypoxic damage, through an immune-regulatory role resulting in the alternative activation of macrophages. By controlling excessive M2 polarization, S100A8/A9 fine-tunes the adaptive response of the kidney to IR-induced AKI ( Chapter 2 ). Conversely, in chronically inflamed kidneys, S100A8/A9 contributes to the development of fibrosis possibly through a direct effect on dedifferentiation and apoptosis in tubular epithelial cells. This effect was independent of S100A8/A9-induced inflammation and recruitment of leukocytes into the kidney ( Chapter 3 ). Instead, TREM-1 is not involved in the amplification of acute renal damage and inflammation in preclinical model of acute kidney injury. Additionally, renal transplanted patients carrying the TREM1 gene variant p.Thr25Ser do not show any association with pathological consequences after transplantation ( Chapter 5 ). TREM-1, however, limits the maladaptive repair post IR-induced AKI, through a direct effect on tubular epithelial mitochondrial homeostasis and energy production, empowering cell cycle progression. The metabolic advantage provided by TREM-1 is indispensable for tubular proliferation, which sustains renal repair and accelerates the recovery from IR ( Chapter 6 ). In the preclinical model of chronic kidney disease TREM-1 and its adapter molecule DAP12 are not involved in the development of renal fibrosis. DAP12, partly through TREM-1, modulates the renal inflammatory response following unilateral ureteral obstruction ( Chapter 7 )
Determinants of acute and chronic renal allograft injury
No full textRenal transplantation researchers have earned big successes by understanding the factors that lead to allorecognition and rejection of solid organ transplants. This knowledge has led to more effective immunosuppressive drug regimens at the cost of an increase in post-transplant infectious diseases and malignancies. Also, with the successes that are acquired with effective immunosuppression, the boundaries of renal transplantation as a therapy have been stretched over the past decades with the introduction of expanded criteria donations, prolonged cold ischemia times, increasing recipient ages and transplantation of immunologically complex cases (e.g. ABO incompatible transplantation). Altogether, this makes both acute, but especially chronic renal allograft failure a true multifactorial disease. This thesis is therefore divided in three parts: factors that define the early post-transplantation period that leads to acute kidney injury of the allograft (Part 1). This early post-transplant period has a large impact on priming of the allo-immune response. In the outpatient setting, the constant interplay between allo-immunity, physiological immune surveillance and immunosupression puts the allograft at risk for rejection, infections and immunosuppressive drug toxicity (Part 2). Ongoing, often subclinical injury to the allograft finally leads to irreversible allograft sclerosis, graft failure and the necessity for new renal replacement therapy (Part 3). Conclusion: This thesis described differences between various renal allograft injuries and their relative impact on graft failure. We introduced novel findings that might contribute to the way we think about the pathogenesis of ischemia-reperfusion injury, allograft rejection, viral immunity and the final common pathway of chronic allograft injury. Besides novel finding, also the reproducibility of hypotheses that were proposed by other research groups was tested in large, independent patient cohorts. This cycle of production and reproduction promotes the science that leads to an improvement in the treatment of patients with a renal transplant
Reduced lung inflammation in TLR2 KO mice early after infection with D39 or PLN
No full text<p><b>Copyright information:</b></p><p>Taken from "Toll-like receptor 2 contributes to antibacterial defence against pneumolysin-deficient pneumococci"</p><p></p><p>Cellular Microbiology 2008;10(1):237-246.</p><p>Published online Jan 2008</p><p>PMCID:PMC2253695.</p><p>© 2007 The Authors Journal compilation © 2007 Blackwell Publishing Ltd</p> Representative lung tissue slides from WT mice (A and C) and TLR2 KO mice (B and D) 6 h after infection with 5 × 10 cfu D39 (A and B) or PLN (C and D). HE staining: magnification 4×. Insets show Ly-6G staining
Experimental Study of Heat Dissipation in Indoor Sports Shoes
No full textAs indoor sports shoes are intensively used in a warm and sweaty environment for periods of up to three consecutive hours, the built-up heat inside is insufficiently released causing warm and perspiring feet. This results in an increased chance of blisters and skin irritations. Experimental research on the ventilation properties of the shoe was done using a controlled heat source, digital thermometer and thermo-graphic camera. A representative set of five volley- and handball shoes were subjected to performance testing to explore possibilities for improvement. This paper will explain the test set-up, present the experiments results, discuss the outcome from the research experiments and present a set of conclusions and recommendations for further developments in footwear ventilation.Design EngineeringIndustrial Design Engineerin
CD14 plays a limited role during influenza A virus infection in vivo
No full textInfluenza A is a single stranded (ss)RNA virus that can cause upper respiratory tract infections that in rare cases may progress to pneumonia. Toll-like receptors (TLRs) and CD14 are receptors which recognize viral proteins and nucleic acid of several viruses. CD14 is required for influenza-induced cytokine production during infection of mouse macrophages. In addition, CD14 was shown to bind ssRNA, suggesting an important role for CD14 during infection with influenza. To investigate the role of CD14 during influenza pneumonia we inoculated WT and CD14 KO mice with a non-lethal dose of a mouse adapted strain of influenza A. CD14 KO mice displayed a reduced viral load in the lungs, 2 and 14 days after infection with influenza. Pulmonary cytokine production in CD14 KO mice was reduced at day 2 and elevated at day 8 compared to WT mice. CD14 deficiency did not influence lymphocyte recruitment or lymphocyte activation in lungs and draining lymph nodes 8 days after infection. These data show that CD14 plays a limited role in host defense against infection with influenz
Monocyte chemoattractant protein 1 contributes to an adequate immune response in influenza pneumonia
No full textMonocyte chemoattractant protein 1 (MCP-1) and its receptor CCR2 have been shown to play an import role in leukocyte recruitment to sites of infection and inflammation. To investigate the role of MCP-1 during infection with influenza we inoculated wild-type (WT) and MCP-1 knockout (KO) mice with a non-lethal dose of a mouse adapted strain of influenza A. Influenza infection of WT mice resulted in a profound increase in pulmonary MCP-1 levels. MCP-1 KO mice had enhanced weight loss and did not fully regain their body weight during the 14-day observation period. In addition, MCP-1 KO mice demonstrated elevated viral loads 8 days after infection, which was accompanied by reduced leukocyte recruitment into the infected lungs, primarily caused by a diminished influx of macrophages and granulocytes. Moreover, pulmonary levels of IgA were reduced in MCP-1 KO mice. The pulmonary concentrations of tumor necrosis factor-alpha, interleukin-6, macrophage inflammatory protein 2 and interferon-gamma were higher in MCP-1 KO mice. This study shows that MCP-1 contributes to an adequate protective immune response against influenza infection in mic
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