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Hikmet Hakan Aydin - One of the best experts on this subject based on the ideXlab platform.

  • TLR 2 gene arg753gln polymorphism is strongly associated with acute rheumatic fever in children
    Journal of Molecular Medicine, 2005
    Co-Authors: Afig Berdeli, Handan Ak Celik, Ruhi Ozyurek, Buket Dogrusoz, Hikmet Hakan Aydin
    Abstract:

    The recently described family of toll-like receptors (TLRs) is a key player in host immunity by mediating inflammatory reactions against a wide range of pathogens. Mutations and polymorphisms in TLRs have revealed the importance of TLRs in human defence against diseases. TLR-2 is reported to interact with different bacterial structures, including lipoproteins, peptidoglycan and lipoteichoic acid. To assess the role of TLR-2 gene polymorphism in acute rheumatic fever (ARF) etiopathology, 61 independent Caucasian Turkish patients and 91 child and 116 adult controls were studied. Antistreptolycin O, C-reactive protein, sedimentation and white blood cell counts were studied to evaluate the clinical characteristics of the patients. Genomic DNA was extracted from peripheral blood using a standard column extraction technique. The Arg753Gln and Arg677Trp polymorphisms were genotyped by polymerase chain reaction (PCR) restriction fragment length polymorphism. The PCR products for the TLR-2 gene were analysed on 1.5% agarose gel pre-stained with ethidium bromide. Compared with healthy adult controls, the Arg753Arg genotype was significantly decreased in the entire group of ARF cases [odds ratio (OR) 0.01, 95% confidence interval (95% CI) 0.0034–0.031, p<0.0001]. Significantly, ARF patients were just 16 times more frequent with Gln allele (OR 15.6, 95% CI 7.87–30.8, p<0.0001). Moreover, evidence for an intensifying effect of the Gln allele was noteworthy when patients with Arg753Gln genotype were compared with healthy controls (OR 97.1, 95% CI 32.5–290, p<0.0001). However, no Arg677Trp polymorphism was detected in either patients or controls. Our data suggest that there is strong evidence for the biological role of TLR-2 in ARF. The common TLR-2 Arg to Gln polymorphism at position 753 significantly contributes to the pathogenesis of ARF. These results will allow the construction of a profile of individuals prone to ARF and may assist in developing new therapies.

  • TLR-2 gene Arg753Gln polymorphism is strongly associated with acute rheumatic fever in children.
    Journal of Molecular Medicine, 2005
    Co-Authors: Afig Berdeli, Handan Ak Celik, Ruhi Ozyurek, Buket Dogrusoz, Hikmet Hakan Aydin
    Abstract:

    The recently described family of toll-like receptors (TLRs) is a key player in host immunity by mediating inflammatory reactions against a wide range of pathogens. Mutations and polymorphisms in TLRs have revealed the importance of TLRs in human defence against diseases. TLR-2 is reported to interact with different bacterial structures, including lipoproteins, peptidoglycan and lipoteichoic acid. To assess the role of TLR-2 gene polymorphism in acute rheumatic fever (ARF) etiopathology, 61 independent Caucasian Turkish patients and 91 child and 116 adult controls were studied. Antistreptolycin O, C-reactive protein, sedimentation and white blood cell counts were studied to evaluate the clinical characteristics of the patients. Genomic DNA was extracted from peripheral blood using a standard column extraction technique. The Arg753Gln and Arg677Trp polymorphisms were genotyped by polymerase chain reaction (PCR) restriction fragment length polymorphism. The PCR products for the TLR-2 gene were analysed on 1.5% agarose gel pre-stained with ethidium bromide. Compared with healthy adult controls, the Arg753Arg genotype was significantly decreased in the entire group of ARF cases [odds ratio (OR) 0.01, 95% confidence interval (95% CI) 0.0034–0.031, p

Biswadev Bishayi - One of the best experts on this subject based on the ideXlab platform.

  • TLR-2 neutralization potentiates microglial M1 to M2 switching by the combinatorial treatment of ciprofloxacin and dexamethasone during S. aureus infection.
    Journal of Neuroimmunology, 2020
    Co-Authors: Biswadev Bishayi
    Abstract:

    Abstract Microglial inflammation plays a pivotal role in the pathogenesis of S. aureus induced brain abscesses. The objective of this study was to regulate microglial activation by the combinatorial treatment of ciprofloxacin either with dexamethasone or celecoxib via targeting M1 and M2 polarization. The antibiotic-immunomodulator combinations were applied either by opening both TLR-2 and GR or neutralizing each of them. Our results confirmed that dexamethasone along with ciprofloxacin attenuated bacterial burden along with ROS production more efficiently than celecoxib combination during TLR-2 neutralization. FACS data indicated microglial M1 to M2 switching that was responsible for the better resolution of microglial inflammation.

  • Dexamethasone exhibits its anti-inflammatory effects in S. aureus induced microglial inflammation via modulating TLR-2 and glucocorticoid receptor expression.
    International Immunopharmacology, 2019
    Co-Authors: Biswadev Bishayi
    Abstract:

    Abstract Microglial inflammation plays crucial role in the pathogenesis of CNS infections including brain abscesses. Staphylococcus aureus (S. aureus) is considered as one of the major causative agents of brain abscesses. Due to the emergence of multidrug resistant bacteria the available treatment options including conventional antibiotics and steroid therapy become ineffective in terms of inflammation regulation which warrants further investigation to resolve this health issue. Microglial TLR-2 plays important roles in the bacterial recognition as well as induction of inflammation whereas glucocorticoid receptor (GR) triggers anti-inflammatory pathways in presence of glucocorticoids (GCs). The main objective of this study was to figure out the interdependency between TLR-2 and GR in presence of exogenous dexamethasone during microglial inflammation as an alternative therapeutic approach. Experiments were done either in TLR-2 neutralized condition or GR blocked condition in presence of dexamethasone. Free radicals production, arginase, superoxide dismutase (SOD), catalase enzyme activities and corticosterone concentration were measured along with Western blot analysis of TLR-2, GR and other inflammatory molecules. The results suggested that dexamethasone pre-treatment in TLR-2 neutralized condition efficiently reduces the inflammatory consequences of S. aureus induced microglial inflammation through up regulating GR expression. During TLR-2 blocking dexamethasone exerted its potent anti-inflammatory activities via suppressing reactive oxygen species (ROS), NO production and up regulating arginase, SOD and catalase activities at the time point of 90 min. Further in-vivo experiments are needed to conclude that dexamethasone could resolve brain inflammation possibly through microglial phenotypic switching from pro-inflammatory M1 to anti-inflammatory M2.

  • A novel CCR-2/TLR-2 triggered signaling in murine peritoneal macrophages intensifies bacterial (Staphylococcus aureus) killing by reactive oxygen species through TNF-R1.
    Immunology Letters, 2017
    Co-Authors: Ajeya Nandi, Biswadev Bishayi
    Abstract:

    Abstract Macrophages are remarkably versatile in their ability to recognize and respond to a wide range of stimuli by expressing a variety of surface and intracellular receptors and triggering multiple signal transduction pathways. The onset of microbial infection is primarily determined by the initial contacts made by the microbes with the host macrophages. Although there prevail a relationship between the chemokine receptor and Toll like receptors during disease, particularly TLR-2 and CCR-2 signaling interdependence on each other has not been yet investigated during acute staphylococcal infection. Thus, the present study was aimed to trace possible interaction between CCR-2 and TLR-2 in peritoneal macrophages during acute Staphylococcus aureus infection. We found that neutralization of CCR-2 attenuates TLR-2 expression and restricts S. aureus burden but TLR-2 neutralization augments CCR-2 expression in macrophages, along with compromised host-derived reactive oxygen species production. S. aureus infection to CCR-2 intact but TLR-2 neutralized macrophages triggered production of IL-1β, TNF-α, IL-6, IFN-γ, MCP-1 and expression of iNOS, TNFR-1 and GPx with concomitant decrease in IL-10 production. Further, study with NG-monomethyl- l -arginine (L-NMMA) [iNOS blocker] and buthionine sulfoximine (BSO) [GPx blocker] revealed that S. aureus infection enhanced TLR-2 expression in CCR-2 intact and TLR-2 neutralized macrophages possibly via iNOS and TNFR-1 up regulation and GPx down regulation. Overall, our data indicate that targeting CCR-2 with neutralizing antibody in the early phase of S. aureus infection could restrict excessive inflammation with less compromised bacterial killing. It certainly would be a therapeutic strategy in S. aureus induced inflammatory and infective diseases.

  • Intracellularly survived Staphylococcus aureus after phagocytosis are more virulent in inducing cytotoxicity in fresh murine peritoneal macrophages utilizing TLR-2 as a possible target.
    Microbial Pathogenesis, 2016
    Co-Authors: Ajeya Nandi, Biswadev Bishayi
    Abstract:

    Abstract Staphylococcus aureus with high virulence potential is contributing to a current public health crisis in both hospital and community settings. TLR-2 and generation of reactive oxygen species (ROS) by phagocytic cells is thought to be an important component of the host’s immunity against S. aureus infection. However, response of S. aureus against modulation of host-derived ROS in absence of TLR-2 during acute staphylococcal infection is still remains unclear. Peritoneal macrophages were pretreated with either inhibitors of superoxide dismutase (SOD) or catalase in presence or absence of anti TLR-2 antibody and were infected with S. aureus strain AG-789. Bacteria were recovered after time dependent phagocytosis; intracellular killing, level and expression of SOD and catalase were measured. Phagocytosed bacteria from respective groups were further used for infection to fresh peritoneal macrophages as well as for in vivo infection. Levels of ROS, cytokine, lysozyme, antioxidant enzymes activity and TLR-2 expression were measured. Results revealed that more bacteria were escaped killing in SOD and catalase inhibitor pretreated TLR-2 neutralized macrophages, found to express more catalase and are antibiotic resistant. Infection of fresh macrophages with S. aureus, recovered from SOD and catalase inhibited TLR-2 neutralized macrophages induced lower ROS, lysozyme and cytokine production and caused increased bacterial count. Furthermore, bacterial antioxidants by modulating host-derived ROS could regulate the cell surface TLR-2 expression in murine peritoneal macrophages. So, in the early phase of infection, TLR-2 participates in the innate immune response and targeting bacterial antioxidants might be useful in the alleviation of Staphylococcus aureus infection.

  • Host antioxidant enzymes and TLR-2 neutralization modulate intracellular survival of Staphylococcus aureus: Evidence of the effect of redox balance on host pathogen relationship during acute staphylococcal infection.
    Microbial Pathogenesis, 2015
    Co-Authors: Ajeya Nandi, Biswadev Bishayi
    Abstract:

    Staphylococcus aureus is an important pathogen in bone disease and innate immune recognition receptor, TLR-2 is reported to be crucial for inflammatory bone loss. Role of TLR-2 in bacterial clearance and cytokine response to S. aureus infection in murine bone marrow macrophages has been reported but the role of host derived ROS in host–pathogen relationship still remains an obvious question. In the present study, blocking of SOD and catalase in TLR-2 neutralized fresh bone marrow cells (FBMC) with Diethyldithiocarbamic acid (DDC) and 3-Amino-1,2,4-triazole (ATZ), separately, during acute S. aureus infection, produces moderate level of ROS and limits inflammation as compared with only TLR-2 non-neutralized condition and leads to decreased bacterial count compared with only TLR-2 neutralized condition. In summary, host SOD and catalase modulates ROS generation, cytokine levels and TLR-2 expression in FBMCs during acute S. aureus infection which might be useful in the alleviation of S. aureus infection and bone loss.

Leticia Morenofierros - One of the best experts on this subject based on the ideXlab platform.

  • expression of toll like receptor TLR 2 TLR 3 TLR 4 and TLR 9 is increased in placentas from patients with preeclampsia
    Archives of Medical Research, 2011
    Co-Authors: Antonio Pineda, Leticia S Verdinteran, Ausencio Camacho, Leticia Morenofierros
    Abstract:

    Background and Aims Few studies have examined the presence of Toll-like receptors (TLRs) in term placentas from women with preeclampsia, such, have focused on TLR-4 and TLR-2 analysis. Whereas an increase in TLR-4 immunostaining has been observed in preeclampsia, it is even higher in placentas with chorioamnionitis compared with normal pregnancy. Expression of TLR-2 has not been associated with preeclampsia. The relationship of TLR-3 and TLR-9, which may recognize dsRNA or DNA, either derived either from microorganisms or from apoptotic cells and thus may be involved with this pathology, has not been studied in term placentas. We undertook this study to determine if there are changes in the expression and localization of TLR-2, TLR-4, TLR-3 and TLR-9 in preeclamptic term placentas as compared with normal placentas. Methods A prospective, cross-sectional and comparative study was done in a group of ten patients with 38–40 gestation weeks, both in preeclamptic and control cases. Immunofluorescence detection of TLRs was performed in samples of placenta and analyzed by confocal microscopy. Results It was observed that TLR-2, TLR-3, TLR-4 and TLR-9 were expressed both in normal and preeclamptic placentas, in the trophoblast, at the vascular endothelium (where TLR-2 and TLR-9 staining was pronounced), and at placental villous stroma, although increased expression was detected in preeclampsia. In addition, co-localization of TLR-2 and TLR-4 as well as of TLR-3 and TL9 was found in the trophoblast. Conclusions TLR-2, -3, -4 and -9 expressions are increased in preeclamptic placentas. However, more studies are required to determine the role of TLRs in pregnancy immunology and to establish its relationship with preeclampsia.

Dmitri V Krysko - One of the best experts on this subject based on the ideXlab platform.

  • severity of doxorubicin induced small intestinal mucositis is regulated by the TLR 2 and TLR 9 pathways
    The Journal of Pathology, 2012
    Co-Authors: Agnieszka Kaczmarek, Brigitta M Brinkman, Liesbeth Heyndrickx, Peter Vandenabeele, Dmitri V Krysko
    Abstract:

    Intestinal mucositis is a serious complication of cancer chemotherapy and radiotherapy; it frequently compromises treatment and dramatically reduces the quality of life of patients. Different approaches to limit the damage to the intestine during anti-cancer therapy have been largely ineffective due to insufficient knowledge of the mechanism of mucositis development. This study aimed to define the role of TLR-2 and TLR-9 in the modulation of small intestinal damage in a model of doxorubicin-induced mucositis. Doxorubicin-induced intestinal damage was verified by a histological score (HS), analysis of leukocyte influx into the lamina propria, and determination of the number of apoptotic cells. Additionally, the activation status of glycogen synthase kinase 3β (GSK-3β) was assessed. Wild-type (WT) mice injected with doxorubicin demonstrated severe intestinal damage (HS 8.0 ± 0.81), reduction of villus length to 43.9% ± 13.7% of original length, and increased influx of leukocytes as compared to vehicle-injected mice (HS 1.33 ± 1.15). The protective effect of TLR-2 or TLR-9 deficiency was associated with a significant decrease of the HS as compared to WT mice. In the ileum, a minor reduction of villus length and a decreased number of infiltrating leukocytes and TUNEL-positive cells was observed. We demonstrate that the TLR-9 antagonist ODN2088 reduces doxorubicin-induced intestinal damage. Furthermore, we show that GSK-3β activity is inhibited in the absence of TLR-2. The protective capacity of GSK-3β suppression was observed in WT mice by inhibiting it with the specific inhibitor SB216763. Overall, our findings demonstrate that the TLR-2/GSK-3β and TLR-9 signalling pathways play a central role in the development of intestinal mucositis and we suggest a new therapeutic strategy for limiting doxorubicin-induced intestinal inflammation. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  • Severity of doxorubicin‐induced small intestinal mucositis is regulated by the TLR‐2 and TLR‐9 pathways
    The Journal of Pathology, 2011
    Co-Authors: Agnieszka Kaczmarek, Brigitta M Brinkman, Liesbeth Heyndrickx, Peter Vandenabeele, Dmitri V Krysko
    Abstract:

    Intestinal mucositis is a serious complication of cancer chemotherapy and radiotherapy; it frequently compromises treatment and dramatically reduces the quality of life of patients. Different approaches to limit the damage to the intestine during anti-cancer therapy have been largely ineffective due to insufficient knowledge of the mechanism of mucositis development. This study aimed to define the role of TLR-2 and TLR-9 in the modulation of small intestinal damage in a model of doxorubicin-induced mucositis. Doxorubicin-induced intestinal damage was verified by a histological score (HS), analysis of leukocyte influx into the lamina propria, and determination of the number of apoptotic cells. Additionally, the activation status of glycogen synthase kinase 3β (GSK-3β) was assessed. Wild-type (WT) mice injected with doxorubicin demonstrated severe intestinal damage (HS 8.0 ± 0.81), reduction of villus length to 43.9% ± 13.7% of original length, and increased influx of leukocytes as compared to vehicle-injected mice (HS 1.33 ± 1.15). The protective effect of TLR-2 or TLR-9 deficiency was associated with a significant decrease of the HS as compared to WT mice. In the ileum, a minor reduction of villus length and a decreased number of infiltrating leukocytes and TUNEL-positive cells was observed. We demonstrate that the TLR-9 antagonist ODN2088 reduces doxorubicin-induced intestinal damage. Furthermore, we show that GSK-3β activity is inhibited in the absence of TLR-2. The protective capacity of GSK-3β suppression was observed in WT mice by inhibiting it with the specific inhibitor SB216763. Overall, our findings demonstrate that the TLR-2/GSK-3β and TLR-9 signalling pathways play a central role in the development of intestinal mucositis and we suggest a new therapeutic strategy for limiting doxorubicin-induced intestinal inflammation. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Jeremy S Duffield - One of the best experts on this subject based on the ideXlab platform.

  • TLR 2 TLR 4 trem 1 signaling pathway is dispensable in inflammatory myeloid cells during sterile kidney injury
    PLOS ONE, 2013
    Co-Authors: Gabriela Campanholle, Kristen Mittelsteadt, Shunsaku Nakagawa, Akio Kobayashi, Sina A Gharib, Jay W Heinecke, Jessica A Hamerman, William A Altemeier, Jeremy S Duffield
    Abstract:

    Inflammatory macrophages are abundant in kidney disease, stimulating repair, or driving chronic inflammation and fibrosis. Damage associated molecules (DAMPs), released from injured cells engage pattern recognition receptors (PRRs) on macrophages, contributing to activation. Understanding mechanisms of macrophage activation during kidney injury may lead to strategies to alleviate chronic disease. We identified Triggering-Receptor-in-Myeloid-cells (TREM)-1, a regulator of TLR signaling, as highly upregulated in kidney inflammatory macrophages and tested the roles of these receptors in macrophage activation and kidney disease. Kidney DAMPs activated macrophages in vitro, independently of TREM-1, but partially dependent on TLR-2/−4, MyD88. In two models of progressive interstitial kidney disease, TREM-1 blockade had no impact on disease or macrophage activation in vivo, but TLR-2/−4, or MyD88 deficiency was anti-inflammatory and anti-fibrotic. When MyD88 was mutated only in the myeloid lineage, however, there was no bearing on macrophage activation or disease progression. Instead, TLR-2/−4 or MyD88 deficiency reduced activation of mesenchyme lineage cells resulting in reduced inflammation and fibrosis, indicating that these pathways play dominant roles in activation of myofibroblasts but not macrophages. To conclude, TREM-1, TLR2/4 and MyD88 signaling pathways are redundant in myeloid cell activation in kidney injury, but the latter appear to regulate activation of mesenchymal cells.