Dataset Information

Roles of TLR/MyD88/MAPK/NF-?B Signaling Pathways in the Regulation of Phagocytosis and Proinflammatory Cytokine Expression in Response to E. faecalis Infection.

ABSTRACT: Enterococcus faecalis is a commensal bacterium residing in the gastrointestinal tract of mammals, but in certain situations it is also an opportunistic pathogen which can cause serious disease. Macrophages have been shown to play a critical role in controlling infections by commensal enterococci and also have an important role in mediating chromosomal instability and promoting colon cancer during high-level enterococcal colonization in genetically susceptible mice. However, the molecular mechanisms involved in the interaction of macrophages with enterococci during infection are not fully understood. In this study, using BMDM and RAW264.7 macrophages we show that enterococcal infection activates ERK, JNK and p38 MAPK as well as NF-?B, and drives polarization of macrophages towards the M1 phenotype. Inhibition of NF-?B activation significantly reduced the expression of TNF-? and IL-1?, as did the inhibition of ERK, JNK and p38 MAPK, although to differing extent. Enterococci-induced activation of these pathways and subsequent cytokine expression was contact dependent, modest compared to activation by E. coli and, required the adaptor protein MyD88. Phagocytosis of enterococci by macrophages was enhanced by preopsonization with E. faecalis antiserum and involved the ERK and JNK signaling pathways, with the adaptor protein MyD88 as an important mediator. This study of the interaction of macrophages with enterococci could provide a foundation for studying the pathogenesis of infection by this opportunistic pathogen and to developing new therapeutic approaches to combat enterococcal infection.

SUBMITTER: Zou J

PROVIDER: S-EPMC4552673 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Roles of TLR/MyD88/MAPK/NF-κB Signaling Pathways in the Regulation of Phagocytosis and Proinflammatory Cytokine Expression in Response to E. faecalis Infection.

Zou Jun J Shankar Nathan N

PloS one 20150828 8

Enterococcus faecalis is a commensal bacterium residing in the gastrointestinal tract of mammals, but in certain situations it is also an opportunistic pathogen which can cause serious disease. Macrophages have been shown to play a critical role in controlling infections by commensal enterococci and also have an important role in mediating chromosomal instability and promoting colon cancer during high-level enterococcal colonization in genetically susceptible mice. However, the molecular mechani ...[more]

PMID: 26317438

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Project description:Toll-like receptor signaling, mediated by functional Toll/interleukin-1 receptor (TIR) domains, plays a critical role in activating the innate immune response responsible for controlling and clearing infection. Bacterial protein mimics of components of this signaling pathway have been identified and function through inhibition of interactions between Toll-like receptors (TLRs) and their adaptor proteins, mediated by TIR domains. A previously uncharacterized gene, which we have named tcpF (for TIR domain-containing protein in E. faecalis) was identified in the genome of Enterococcus faecalis V583, and predicted to encode a protein resembling mammalian and bacterial TIR proteins. We overexpressed and purified TcpF from E. coli and found that the recombinant protein could bind to phosphatidylinositol phosphates in vitro, suggesting a mechanism by which TcpF may be anchored to the plasma membrane in close proximity to TIR domains of TLRs and adaptor proteins. Purified TcpF was also found to interact specifically with the TIR adaptor protein MyD88, and this interaction was dependent on the BB loop domain in the Box 2 region of TcpF. Despite no evidence of TcpF being a secreted protein, recombinant TcpF was effectively able to enter RAW264.7 cells in vitro although the mechanism by which this occurs remains to be determined. Overexpression of TcpF in mammalian cells suppressed the NF-κB activation induced by bacterial lipoteichoic acid. A mutant lacking the tcpF gene was attenuated for survival in macrophages, with increased ability to activate NF-κB compared to the wild type strain. Complementation in trans restored growth, and inhibition of NF-κB, to that of wild type levels. No appreciable difference in bacterial persistence, dissemination or pathogenesis was observed between the wild type and mutant in a mouse peritonitis model however, which suggested either a subtle role for TcpF or functional overlap with other redundant factor(s) in this virulence model.

Project description:In response to danger signals, macrophages rapidly produce many inflammatory cytokines that trigger the cascade release of inflammatory mediators, leading to tissue damage, which is an important cause of clinical manifestations of syphilis at all stages. However, we still know very little about the specific mechanism of this process. Tp0768 is an infection-stage-dependent antigen that plays an important role in the infection of Treponema pallidum. In this study, we demonstrated that Tp0768 stimulation of macrophages can cause IL-1β, IL-6, and IL-8 mRNA expression levels to increase in a dose- and time-dependent manner. Further research showed that Tp0768 activated ER stress and the ROS/NF-κB pathway in macrophages. Inhibition of ER stress and the ROS/NF-κB pathway inhibited the expression of IL-1β, IL-6, and IL-8 induced by Tp0768. In addition, pretreatment with a PERK pathway inhibitor significantly reduced the expression of the NF-κB and JNK pathways, while also downregulating the expression of IL-1β, IL-6, and IL-8. Tp0768 stimulation can activate IRE1α/XBP-1 signaling and participate in the induction of inflammatory cytokines through the JNK pathway. These findings indicate that Tp0768 promotes the secretion of proinflammatory cytokines IL-1β, IL-6, and IL-8 by macrophages through ER stress and the ROS/NF-κB pathway, which are also involved in the activation of the NF-κB and JNK pathways that are induced by the PERK pathway and activation of IRE1α/XBP-1 signaling. KEY POINTS: • This study found for the first time that the recombinant Treponema pallidum protein Tp0768 promotes the production of IL-1β, IL-6, and IL-8 by macrophages through ER stress. • Recombinant Treponema pallidum protein Tp0768 regulates the ROS/NF-κB pathway through ER stress. • ER stress-related pathway PERK induces the expression of IL-1β, IL-6, and IL-8 by activating the NF-κB pathway and the JNK pathway. • IRE1α can induce the splicing of XBP-1mRNA and activate the JNK pathway.

Dataset Information

Roles of TLR/MyD88/MAPK/NF-?B Signaling Pathways in the Regulation of Phagocytosis and Proinflammatory Cytokine Expression in Response to E. faecalis Infection.

Publications

Roles of TLR/MyD88/MAPK/NF-κB Signaling Pathways in the Regulation of Phagocytosis and Proinflammatory Cytokine Expression in Response to E. faecalis Infection.

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