scholarly journals SalmonellaFimbrial Protein FimH Is Involved in Expression of Proinflammatory Cytokines in a Toll-Like Receptor 4-Dependent Manner

2019 ◽  
Vol 87 (3) ◽  
Author(s):  
Kei-ichi Uchiya ◽  
Yurie Kamimura ◽  
Ayumi Jusakon ◽  
Toshiaki Nikai
Keyword(s):  
Proinflammatory Cytokines ◽  
Mitogen Activated Protein Kinase ◽  
Hek293 Cells ◽  
Dependent Manner ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Content Type ◽  
Type 1 Fimbriae ◽  
Serovar Typhimurium

ABSTRACTType 1 fimbriae are proteinaceous filamentous structures present on bacterial surfaces and are mainly composed of the major fimbrial protein subunit FimA and the adhesive protein FimH, which is located at the tip of the fimbrial shaft. Here, we investigated the involvement of type 1 fimbriae in the expression of proinflammatory cytokines in macrophages infected withSalmonella entericaserovar Typhimurium. The level of interleukin-1β (IL-1β) mRNA was lower in macrophages infected withfimAorfimHmutant strains than in those infected with wild-typeSalmonella. Treatment of macrophages with purified recombinant FimH protein, but not FimA, resulted in the activation of the mitogen-activated protein kinase and nuclear factor κB signaling pathways, leading to the expression of not only IL-1β but also other proinflammatory cytokines, such as IL-6 and tumor necrosis factor alpha. However, FimH carrying an N-terminal region deletion or heat-treated FimH did not show such effects. The expression of FimH-induced IL-1β was inhibited by treatment with the Toll-like receptor 4 (TLR4) inhibitor TAK-242 but not by treatment with polymyxin B, a lipopolysaccharide antagonist. Furthermore, FimH treatment stimulated HEK293 cells expressing TLR4 and MD-2/CD14 but did not stimulate HEK293 cells expressing only TLR4. Collectively, FimH is a pathogen-associated molecular pattern ofS. entericaserovar Typhimurium that is recognized by TLR4 in the presence of MD-2 and CD14 and plays a significant role in the expression of proinflammatory cytokines inSalmonella-infected macrophages.

scholarly journals Activation of Porcine Alveolar Macrophages byActinobacillus pleuropneumoniaeLipopolysaccharide via the Toll-Like Receptor 4/NF-κB-Mediated Pathway

2017 ◽  
Vol 86 (3) ◽  
Author(s):  
Bi Li ◽  
Jing Fang ◽  
Zhicai Zuo ◽  
Sirui Yin ◽  
Tingting He ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Alveolar Macrophages ◽  
Intracellular Signaling ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Immunological Responses ◽  
Pathogen Invasion ◽  
Porcine Contagious Pleuropneumonia

ABSTRACTActinobacillus pleuropneumoniaeis the causative agent of porcine contagious pleuropneumonia. Overproduction of proinflammatory cytokines, like interleukin-1β (IL-1β), IL-6, tumor necrosis factor alpha, and resistin, in the lung is an important feature ofA. pleuropneumoniaeinfection. These proinflammatory cytokines enhance inflammatory and immunological responses. However, the mechanism that leads to cytokine production remains unclear. As a major virulence factor ofA. pleuropneumoniae, lipopolysaccharide (LPS) may act as a potent stimulator of Toll-like receptor 4 (TLR4), triggering a number of intracellular signaling pathways that lead to the synthesis of proinflammatory cytokines. Porcine alveolar macrophages (PAMs) are the first line of defense against pathogenic microbes during pathogen invasion. The results of the present study demonstrate thatA. pleuropneumoniaeLPS induces PAMs to produce inflammatory cytokines in time- and dose-dependent manners. Moreover, PAMs were activated byA. pleuropneumoniaeLPS, resulting in upregulation of signaling molecules, including TLR4, MyD88, TRIF-related adaptor molecule, and NF-κB. In contrast, the activation effects ofA. pleuropneumoniaeLPS on PAMs could be suppressed by specific inhibitors, like small interfering RNA and Bay11-7082. Taken together, our data indicate thatA. pleuropneumoniaeLPS can induce PAMs to produce proinflammatory cytokines via the TLR4/NF-κB-mediated pathway. These findings partially reveal the mechanism of the overproduction of proinflammatory cytokines in the lungs of swine withA. pleuropneumoniaeinfection and may provide targets for the prevention ofA. pleuropneumoniae-induced pneumonia. All the data could be used as a reference for the pathogenesis of respiratory infection.

scholarly journals Toll-Like Receptor 4 Agonistic Antibody Promotes Host Defense against Chronic Pseudomonas aeruginosa Lung Infection in Mice

2016 ◽  
Vol 84 (7) ◽  
pp. 1986-1993 ◽  
Author(s):  
Shigeki Nakamura ◽  
Naoki Iwanaga ◽  
Masafumi Seki ◽  
Kenji Fukudome ◽  
Kazuhiro Oshima ◽  
...  
Keyword(s):  
Immune Response ◽  
Pseudomonas Aeruginosa ◽  
Neutrophil Recruitment ◽  
Dependent Manner ◽  
Bacterial Clearance ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Content Type ◽  
Opsonophagocytic Killing

Chronic lower respiratory tract infection withPseudomonas aeruginosais difficult to treat due to enhanced antibiotic resistance and decreased efficacy of drug delivery to destroyed lung tissue. To determine the potential for restorative immunomodulation therapies, we evaluated the effect of Toll-like receptor 4 (TLR4) stimulation on the host immune response toPseudomonasinfection in mice. We implanted sterile plastic tubes precoated withP. aeruginosain the bronchi of mice, administered the TLR4/MD2 agonistic monoclonal antibody UT12 intraperitoneally every week, and subsequently analyzed the numbers of viable bacteria and inflammatory cells and the levels of cytokines. We also performed flow cytometry-based phagocytosis and opsonophagocytic killing assaysin vitrousing UT12-treated murine peritoneal neutrophils. UT12-treated mice showed significantly enhanced bacterial clearance, increased numbers of Ly6G+neutrophils, and increased concentrations of macrophage inflammatory protein 2 (MIP-2) in the lungs (P< 0.05). Depletion of CD4+T cells eliminated the ability of the UT12 treatment to improve bacterial clearance and promote neutrophil recruitment and MIP-2 production. Additionally, UT12-pretreated peritoneal neutrophils exhibited increased opsonophagocytic killing activity via activation of the serine protease pathway, specifically neutrophil elastase activity, in a TLR4-dependent manner. These data indicated that UT12 administration significantly augmented the innate immune response against chronic bacterial infection, in part by promoting neutrophil recruitment and bactericidal function.

scholarly journals Lipopolysaccharides Belonging to Different Salmonella Serovars Are Differentially Capable of Activating Toll-Like Receptor 4

2014 ◽  
Vol 82 (11) ◽  
pp. 4553-4562 ◽  
Author(s):  
Daniela Chessa ◽  
Luisella Spiga ◽  
Nicola De Riu ◽  
Paola Delaconi ◽  
Vittorio Mazzarello ◽  
...  
Keyword(s):  
Immune Response ◽  
Salmonella Enterica ◽  
Systemic Infection ◽  
Embryonic Cell ◽  
Limited Information ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Content Type ◽  
Serovar Typhimurium

ABSTRACTSalmonella entericasubsp.entericaserovar (serotype) Abortusovis is a member of theEnterobacteriaceae. This serotype is naturally restricted to ovine species and does not infect humans. Limited information is available about the immune response of sheep toS. Abortusovis.S. Abortusovis, likeSalmonella entericasubsp.entericaserovar Typhi, causes a systemic infection in which, under natural conditions, animals are not able to raise a rapid immune response. Failure to induce the appropriate response allows pathogens to reach the placenta and results in an abortion. Lipopolysaccharides (LPSs) are pathogen-associated molecular patterns (PAMPs) that are specific to bacteria and are not synthesized by the host. Toll-like receptors (TLRs) are a family of receptors that specifically recognize PAMPs. As a first step, we were able to identify the presence of Toll-like receptor 4 (TLR4) on the ovine placenta by using an immunohistochemistry technique. To our knowledge, this is the first work describing the interaction betweenS. Abortusovis LPS and TLR4. Experiments using an embryonic cell line (HEK293) transfected with human and ovine TLR4s showed a reduction of interleukin 8 (IL-8) production byS. Abortusovis andSalmonella entericasubsp.entericaserovar Paratyphi upon LPS stimulation compared toSalmonella entericasubsp.entericaserovar Typhimurium. Identical results were observed using heat-killed bacteria instead of LPS. Based on data obtained with TLR4in vitrostimulation, we demonstrated that the serotypeS. Abortusovis is able to successfully evade the immune system whereasS. Typhimurium and other serovars fail to do so.

scholarly journals FimA, FimF, and FimH Are Necessary for Assembly of Type 1 Fimbriae on Salmonella enterica Serovar Typhimurium

2012 ◽  
Vol 80 (9) ◽  
pp. 3289-3296 ◽  
Author(s):  
Sarah A. Zeiner ◽  
Brett E. Dwyer ◽  
Steven Clegg
Keyword(s):  
Salmonella Enterica ◽  
Salmonella Enterica Serovar Typhimurium ◽  
Food Poisoning ◽  
Enteric Bacteria ◽  
Transcriptional Unit ◽  
Content Type ◽  
E Coli ◽  
Type 1 Fimbriae ◽  
Serovar Typhimurium

ABSTRACTSalmonella entericaserovar Typhimurium is a Gram-negative member of the familyEnterobacteriaceaeand is a common cause of bacterial food poisoning in humans. The fimbrial appendages are found on the surface of many enteric bacteria and enable the bacteria to bind to eukaryotic cells.S. Typhimurium type 1 fimbriae are characterized by mannose-sensitive hemagglutination and are assembled via the chaperone/usher pathway.S. Typhimurium type 1 fimbrial proteins are encoded by thefimgene cluster (fimAICDHFZYW), withfimAICDHFexpressed as a single transcriptional unit. The structural components of the fimbriae are FimA (major subunit), FimI, FimH (adhesin), and FimF (adaptor). In order to determine which components are required for fimbrial formation inS. Typhimurium, mutations infimA,fimI,fimH, andfimFwere constructed and examined for their ability to produce surface-assembled fimbriae.S. Typhimurium SL1344ΔfimA, -ΔfimH, and -ΔfimFmutants were unable to assemble fimbriae, indicating that these genes are necessary for fimbrial production inS. Typhimurium. However, SL1344ΔfimIwas able to assemble fimbriae. InEscherichia colitype 1 and Pap fimbriae, at least two adaptors are expressed in addition to the adhesins. However,E. colitype 1 and Pap fimbriae have been reported to be able to assemble fimbriae in the absence of these proteins. These results suggest differences between theS. Typhimurium type 1 fimbrial system and theE. colitype 1 and Pap fimbrial systems.

scholarly journals Interaction between Ebola Virus Glycoprotein and Host Toll-Like Receptor 4 Leads to Induction of Proinflammatory Cytokines and SOCS1

2009 ◽  
Vol 84 (1) ◽  
pp. 27-33 ◽  
Author(s):  
Atsushi Okumura ◽  
Paula M. Pitha ◽  
Akihiko Yoshimura ◽  
Ronald N. Harty
Keyword(s):  
Proinflammatory Cytokines ◽  
Ebola Virus ◽  
Cytokine Signaling ◽  
Dependent Manner ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Monocytic Cell ◽  
Monocytic Cell Line ◽  
Virus Glycoprotein ◽  
Cytokines And Chemokines

ABSTRACT Ebola virus initially targets monocytes and macrophages, which can lead to the release of proinflammatory cytokines and chemokines. These inflammatory cytokines are thought to contribute to the development of circulatory shock seen in fatal Ebola virus infections. Here we report that host Toll-like receptor 4 (TLR4) is a sensor for Ebola virus glycoprotein (GP) on virus-like particles (VLPs) and that resultant TLR4 signaling pathways lead to the production of proinflammatory cytokines and suppressor of cytokine signaling 1 (SOCS1) in a human monocytic cell line and in HEK293-TLR4/MD2 cells stably expressing the TLR4/MD2 complex. Ebola virus GP was found to interact with TLR4 by immunoprecipitation/Western blot analyses, and Ebola virus GP on VLPs was able to stimulate expression of NF-κB in a TLR4-dependent manner. Interestingly, we found that budding of Ebola virus VLPs was more pronounced in TLR4-stimulated cells than in unstimulated control cells. In sum, these findings identify the host innate immune protein TLR4 as a sensor for Ebola virus GP which may play an important role in the immunopathogenesis of Ebola virus infection.

scholarly journals Phosphothreonine Lyase Promotes p65 Degradation in a Mitogen-Activated Protein Kinase/Mitogen- and Stress-Activated Protein Kinase 1-Dependent Manner

2018 ◽  
Vol 87 (1) ◽  
Author(s):  
Mingyu Hou ◽  
Wenhui Wang ◽  
Feizi Hu ◽  
Yuanxing Zhang ◽  
Dahai Yang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Pathogenic Bacteria ◽  
Critical Role ◽  
Nuclear Factor Κb ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Content Type ◽  
Catalytic Active Site ◽  
Mitogen Activated Protein

ABSTRACT Bacterial phosphothreonine lyases have been identified to be type III secretion system (T3SS) effectors that irreversibly dephosphorylate host mitogen-activated protein kinase (MAPK) signaling to promote infection. However, the effects of phosphothreonine lyase on nuclear factor κB (NF-κB) signaling remain largely unknown. In this study, we detected significant phosphothreonine lyase-dependent p65 degradation during Edwardsiella piscicida infection in macrophages, and this degradative effect was blocked by the protease inhibitor MG132. Further analysis revealed that phosphothreonine lyase promotes the dephosphorylation and ubiquitination of p65 by inhibiting the phosphorylation of mitogen- and stress-activated protein kinase-1 (MSK1) and by inhibiting the phosphorylation of extracellular signal-related kinase 1/2 (ERK1/2), p38α, and c-Jun N-terminal kinase (JNK). Moreover, we revealed that the catalytic active site of phosphothreonine lyase plays a critical role in regulating the MAPK-MSK1-p65 signaling axis. Collectively, the mechanism described here expands our understanding of the pathogenic effector in not only regulating MAPK signaling but also regulating p65. These findings uncover a new mechanism by which pathogenic bacteria overcome host innate immunity to promote pathogenesis.

Pneumococcal DNA-binding proteins released through autolysis induce the production of proinflammatory cytokines via toll-like receptor 4

2018 ◽  
Vol 325 ◽  
pp. 14-22 ◽  
Author(s):  
Kosuke Nagai ◽  
Hisanori Domon ◽  
Tomoki Maekawa ◽  
Masataka Oda ◽  
Takumi Hiyoshi ◽  
...  
Keyword(s):  
Dna Binding ◽  
Proinflammatory Cytokines ◽  
Binding Proteins ◽  
Dna Binding Proteins ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4

scholarly journals Dectin-1 Stimulation of Hematopoietic Stem and Progenitor Cells Occurs In Vivo and Promotes Differentiation Toward Trained Macrophages via an Indirect Cell-Autonomous Mechanism

mBio ◽  
2020 ◽  
Vol 11 (3) ◽  
Author(s):  
Cristina Bono ◽  
Alba Martínez ◽  
Javier Megías ◽  
Daniel Gozalbo ◽  
Alberto Yáñez ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Candida Albicans ◽  
Progenitor Cells ◽  
Recipient Mouse ◽  
Dependent Manner ◽  
Toll Like Receptor ◽  
Hematopoietic Stem ◽  
Content Type ◽  
Stem And Progenitor Cells

ABSTRACT Toll-like receptor (TLR) agonists drive hematopoietic stem and progenitor cells (HSPCs) to differentiate along the myeloid lineage. In this study, we used an HSPC transplantation model to investigate the possible direct interaction of β-glucan and its receptor (dectin-1) on HSPCs in vivo. Purified HSPCs from bone marrow of B6Ly5.1 mice (CD45.1 alloantigen) were transplanted into dectin-1−/− mice (CD45.2 alloantigen), which were then injected with β-glucan (depleted zymosan). As recipient mouse cells do not recognize the dectin-1 agonist injected, interference by soluble mediators secreted by recipient cells is negligible. Transplanted HSPCs differentiated into macrophages in response to depleted zymosan in the spleens and bone marrow of recipient mice. Functionally, macrophages derived from HSPCs exposed to depleted zymosan in vivo produced higher levels of inflammatory cytokines (tumor necrosis factor alpha [TNF-α] and interleukin 6 [IL-6]). These results demonstrate that trained immune responses, already described for monocytes and macrophages, also take place in HSPCs. Using a similar in vivo model of HSPC transplantation, we demonstrated that inactivated yeasts of Candida albicans induce differentiation of HSPCs through a dectin-1- and MyD88-dependent pathway. Soluble factors produced following exposure of HSPCs to dectin-1 agonists acted in a paracrine manner to induce myeloid differentiation and to influence the function of macrophages derived from dectin-1-unresponsive or β-glucan-unexposed HSPCs. Finally, we demonstrated that an in vitro transient exposure of HSPCs to live C. albicans cells, prior to differentiation, is sufficient to induce a trained phenotype of the macrophages they produce in a dectin-1- and Toll-like receptor 2 (TLR2)-dependent manner. IMPORTANCE Invasive candidiasis is an increasingly frequent cause of serious and often fatal infections. Understanding host defense is essential to design novel therapeutic strategies to boost immune protection against Candida albicans. In this article, we delve into two new concepts that have arisen over the last years: (i) the delivery of myelopoiesis-inducing signals by microbial components directly sensed by hematopoietic stem and progenitor cells (HSPCs) and (ii) the concept of “trained innate immunity” that may also apply to HSPCs. We demonstrate that dectin-1 ligation in vivo activates HSPCs and induces their differentiation to trained macrophages by a cell-autonomous indirect mechanism. This points to new mechanisms by which pathogen detection by HSPCs may modulate hematopoiesis in real time to generate myeloid cells better prepared to deal with the infection. Manipulation of this process may help to boost the innate immune response during candidiasis.

Sign in / Sign up

Export Citation Format

Share Document