scholarly journals Mycobacteria tuberculosis PPE36 modulates host inflammation by promoting E3 ligase Smurf1-mediated MyD88 degradation

2021 ◽  
Author(s):  
Zhangli Peng ◽  
Yan Yue ◽  
Sidong Xiong
Keyword(s):  
Immune Responses ◽  
Inflammatory Responses ◽  
Treatment Strategies ◽  
E3 Ligase ◽  
Host Immune Responses ◽  
Virulent Strains ◽  
A Cell ◽  
Underlying Mechanisms ◽  
Mycobacteria Tuberculosis ◽  
Myd88 Protein

Mycobacterium tuberculosis (Mtb) PPE36, a cell-wall associated protein is highly specific and conserved for the Mtb complex group. Although it has been proven essential for iron utilization, little is known about the role of PPE36 in regulating host immune responses. Here we exhibited that PPE36 preferentially enriched in Mtb virulent strains, and could efficiently inhibit host inflammatory responses and increase bacterial loads both in mycobacterium-infected macrophages and mice. In exploring the underlying mechanisms, we found that PPE36 could robustly inhibit the activation of inflammatory NF-κB and MAPK (ERK, p38 and JNK) pathways by promoting E3 ligase Smurf1-mediated ubiquitination and proteasomal degradation of MyD88 protein. Our research revealed a previously unknown function of PPE36 on modulating host immune responses, and provided some clues to the development of novel tuberculosis treatment strategies based on immune regulation.

scholarly journals Probing the Unknowns in Cytokinin-Mediated Immune Defense in Arabidopsis with Systems Biology Approaches

2014 ◽  
Vol 8 ◽  
pp. BBI.S13462 ◽  
Author(s):  
Muhammad Naseem ◽  
Meik Kunz ◽  
Thomas Dandekar
Keyword(s):  
Systems Biology ◽  
Immune Responses ◽  
Protein Interactions ◽  
Immune Defense ◽  
Immune Functions ◽  
Protein Protein Interactions ◽  
Cytokinin Signaling ◽  
Host Immune Responses ◽  
Arabidopsis Protein ◽  
Underlying Mechanisms

Plant hormones involving salicylic acid (SA), jasmonic acid (JA), ethylene (Et), and auxin, gibberellins, and abscisic acid (ABA) are known to regulate host immune responses. However, plant hormone cytokinin has the potential to modulate defense signaling including SA and JA. It promotes plant pathogen and herbivore resistance; underlying mechanisms are still unknown. Using systems biology approaches, we unravel hub points of immune interaction mediated by cytokinin signaling in Arabidopsis. High-confidence Arabidopsis protein—protein interactions (PPI) are coupled to changes in cytokinin-mediated gene expression. Nodes of the cellular interactome that are enriched in immune functions also reconstitute sub-networks. Topological analyses and their specific immunological relevance lead to the identification of functional hubs in cellular interactome. We discuss our identified immune hubs in light of an emerging model of cytokinin-mediated immune defense against pathogen infection in plants.

scholarly journals Staphylococcus aureus synthesizes adenosine to escape host immune responses

2009 ◽  
Vol 206 (11) ◽  
pp. 2417-2427 ◽  
Author(s):  
Vilasack Thammavongsa ◽  
Justin W. Kern ◽  
Dominique M. Missiakas ◽  
Olaf Schneewind
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Immune Responses ◽  
Virulence Factor ◽  
Adenosine Monophosphate ◽  
Healthy Individuals ◽  
Subsequent Formation ◽  
Host Immune Responses ◽  
A Cell ◽  
Exogenous Supply

Staphylococcus aureus infects hospitalized or healthy individuals and represents the most frequent cause of bacteremia, treatment of which is complicated by the emergence of methicillin-resistant S. aureus. We examined the ability of S. aureus to escape phagocytic clearance in blood and identified adenosine synthase A (AdsA), a cell wall–anchored enzyme that converts adenosine monophosphate to adenosine, as a critical virulence factor. Staphylococcal synthesis of adenosine in blood, escape from phagocytic clearance, and subsequent formation of organ abscesses were all dependent on adsA and could be rescued by an exogenous supply of adenosine. An AdsA homologue was identified in the anthrax pathogen, and adenosine synthesis also enabled escape of Bacillus anthracis from phagocytic clearance. Collectively, these results suggest that staphylococci and other bacterial pathogens exploit the immunomodulatory attributes of adenosine to escape host immune responses.

scholarly journals GABA transporter sustains IL-1β production in macrophages

2021 ◽  
Vol 7 (15) ◽  
pp. eabe9274
Author(s):  
Yaoyao Xia ◽  
Fang He ◽  
Xiaoyan Wu ◽  
Bie Tan ◽  
Siyuan Chen ◽  
...  
Keyword(s):  
Immune Responses ◽  
High Fat Diet ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
High Fat ◽  
Gaba Transporter ◽  
Host Immune Responses ◽  
Diet Induced Obesity

Accumulating evidence shows that nervous system governs host immune responses; however, how γ-aminobutyric acid (GABA)ergic system shapes the function of innate immune cells is poorly defined. Here, we demonstrate that GABA transporter (GAT2) modulates the macrophage function. GAT2 deficiency lowers the production of interleukin-1β (IL-1β) in proinflammatory macrophages. Mechanistically, GAT2 deficiency boosts the betaine/S-adenosylmethionine (SAM)/hypoxanthine metabolic pathway to inhibit transcription factor KID3 expression through the increased DNA methylation in its promoter region. KID3 regulates oxidative phosphorylation (OXPHOS) via targeting the expression of OXPHOS-related genes and is also critical for NLRP3–ASC–caspase-1 complex formation. Likewise, GAT2 deficiency attenuates macrophage-mediated inflammatory responses in vivo, including lipopolysaccharide-induced sepsis, infection-induced pneumonia, and high-fat diet-induced obesity. Together, we propose that targeting GABAergic system (e.g., GABA transporter) could provide previously unidentified therapeutic opportunities for the macrophage-associated diseases.

Magnoflorine Enhances LPS-Activated Pro-Inflammatory Responses via MyD88-Dependent Pathways in U937 Macrophages

Planta Medica ◽  
2018 ◽  
Vol 84 (17) ◽  
pp. 1255-1264 ◽  
Author(s):  
Md. Areeful Haque ◽  
Ibrahim Jantan ◽  
Hemavathy Harikrishnan ◽  
Siti Mariam Abdul Wahab
Keyword(s):  
Immune Responses ◽  
Inflammatory Mediators ◽  
Inflammatory Responses ◽  
Akt Signaling ◽  
Mrna Transcription ◽  
Tnf Α ◽  
Cox 2 ◽  
Underlying Mechanisms ◽  
Signaling Activation ◽  
Specific Inhibitors

AbstractMagnoflorine, a major bioactive metabolite isolated from Tinospora crispa, has been reported for its diverse biochemical and pharmacological properties. However, there is little report on its underlying mechanisms of action on immune responses, particularly on macrophage activation. In this study, we aimed to investigate the effects of magnoflorine, isolated from T. crispa on the pro-inflammatory mediators generation induced by LPS and the concomitant NF-κB, MAPKs, and PI3K-Akt signaling pathways in U937 macrophages. Differentiated U937 macrophages were treated with magnoflorine and the release of pro-inflammatory mediators was evaluated through ELISA, while the relative mRNA expression of the respective mediators was quantified through qRT-PCR. Correspondingly, western blotting was executed to observe the modulatory effects of magnoflorine on the expression of various markers related to NF-κB, MAPK and PI3K-Akt signaling activation in LPS-primed U937 macrophages. Magnoflorine significantly enhanced the upregulation of TNF-α, IL-1β, and PGE2 production as well as COX-2 protein expression. Successively, magnoflorine prompted the mRNA transcription level of these pro-inflammatory mediators. Magnoflorine enhanced the NF-κB activation by prompting p65, IκBα, and IKKα/β phosphorylation as well as IκBα degradation. Besides, magnoflorine treatments concentration-dependently augmented the phosphorylation of JNK, ERK, and p38 MAPKs as well as Akt. The immunoaugmenting effects were further confirmed by investigating the effects of magnoflorine on specific inhibitors, where the treatment with specific inhibitors of NF-κB, MAPKs, and PI3K-Akt proficiently blocked the magnoflorine-triggered TNF-α release and COX-2 expression. Magnoflorine furthermore enhanced the MyD88 and TLR4 upregulation. The results suggest that magnoflorine has high potential on augmenting immune responses.

scholarly journals Eosinophils and Bacteria, the Beginning of a Story

2021 ◽  
Vol 22 (15) ◽  
pp. 8004
Author(s):  
Edna Ondari ◽  
Esther Calvino-Sanles ◽  
Nicholas J. First ◽  
Monica C. Gestal
Keyword(s):  
Immune Responses ◽  
Respiratory Tract ◽  
Bacterial Infections ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Current Knowledge ◽  
Parasitic Infections ◽  
Th2 Responses ◽  
A Cell ◽  
Anti Inflammatory

Eosinophils are granulocytes primarily associated with TH2 responses to parasites or immune hyper-reactive states, such as asthma, allergies, or eosinophilic esophagitis. However, it does not make sense from an evolutionary standpoint to maintain a cell type that is only specific for parasitic infections and that otherwise is somehow harmful to the host. In recent years, there has been a shift in the perception of these cells. Eosinophils have recently been recognized as regulators of immune homeostasis and suppressors of over-reactive pro-inflammatory responses by secreting specific molecules that dampen the immune response. Their role during parasitic infections has been well investigated, and their versatility during immune responses to helminths includes antigen presentation as well as modulation of T cell responses. Although it is known that eosinophils can present antigens during viral infections, there are still many mechanistic aspects of the involvement of eosinophils during viral infections that remain to be elucidated. However, are eosinophils able to respond to bacterial infections? Recent literature indicates that Helicobacter pylori triggers TH2 responses mediated by eosinophils; this promotes anti-inflammatory responses that might be involved in the long-term persistent infection caused by this pathogen. Apparently and on the contrary, in the respiratory tract, eosinophils promote TH17 pro-inflammatory responses during Bordetella bronchiseptica infection, and they are, in fact, critical for early clearance of bacteria from the respiratory tract. However, eosinophils are also intertwined with microbiota, and up to now, it is not clear if microbiota regulates eosinophils or vice versa, or how this connection influences immune responses. In this review, we highlight the current knowledge of eosinophils as regulators of pro and anti-inflammatory responses in the context of both infection and naïve conditions. We propose questions and future directions that might open novel research avenues in the future.

scholarly journals Ostertagia ostertagi Mediates Early Host Immune Responses via Macrophage and Toll-Like Receptor Pathways

2021 ◽  
Vol 89 (6) ◽  
Author(s):  
Mariam Bakshi ◽  
Deborah Hebert ◽  
Connor Gulbronson ◽  
Gary Bauchan ◽  
Wenbin Tuo ◽  
...  
Keyword(s):  
Immune Responses ◽  
Time Course ◽  
Mononuclear Cells ◽  
Inflammatory Responses ◽  
Peripheral Blood Mononuclear ◽  
Necrosis Factor Alpha ◽  
Ostertagia Ostertagi ◽  
Host Immune Responses ◽  
Tnf Α ◽  
Anti Inflammatory

ABSTRACT Ostertagia ostertagi is an abomasal parasite with significant economic impact on the cattle industry. Early host immune responses are poorly understood. Here, we examined time course expression of Toll-like receptors (TLRs) in peripheral blood mononuclear cells (PBMC) during infection where PBMC macrophages (Mϕ) generated both pro- and anti-inflammatory responses when incubated with excretory/secretory products (ESP) from fourth-stage larvae (OoESP-L4) or adult worms (OoESP-Ad). First, changes in cell morphology clearly showed that both OoESP-L4 and OoESP-Ad activated PBMC-Mϕ in vitro, resulting in suppressed CD40 and increased CD80 expression. Expression of mRNAs for TLR1, -4, -5, and -7 peaked 7 days postinfection (dpi) (early L4), decreased by 19 dpi (postemergent L4 and adults) and then increased at 27 dpi (late adults). The proinflammatory cytokine tumor necrosis factor alpha (TNF-α) (transcript and protein) increased in the presence of OoESP-Ad, and the anti-inflammatory cytokine interleukin 10 (IL-10) (protein) decreased in the presence of OoESP-L4 or OoESP-Ad; however, IL-10 mRNA was upregulated, and IL-6 (protein) was downregulated by OoESP-L4. When PBMC-Mϕ were treated with ligands for TLR4 or TLR5 in combination with OoESP-Ad, the transcripts for TNF-α, IL-1, IL-6, and IL-10 were significantly downregulated relative to treatment with TLR4 and TLR5 ligands only. However, the effects of TLR2 ligand and OoESP-Ad were additive, but only at the lower concentration. We propose that O. ostertagi L4 and adult worms utilize competing strategies via TLRs and Mϕ to confuse the immune system, which allows the worm to evade the host innate responses.

scholarly journals Multifaceted Roles of Chemokines and Chemokine Receptors in Tumor Immunity

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 6132
Author(s):  
Kazuhiko Matsuo ◽  
Osamu Yoshie ◽  
Takashi Nakayama
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Tumor Immunity ◽  
Immune Cells ◽  
Chemokine Receptors ◽  
Th17 Cells ◽  
Inflammatory Responses ◽  
T Cell Subsets ◽  
Th2 Cells ◽  
Host Immune Responses

Various immune cells are involved in host tumor immune responses. In particular, there are many T cell subsets with different roles in tumor immunity. T-helper (Th) 1 cells are involved in cellular immunity and thus play the major role in host anti-tumor immunity by inducing and activating cytotoxic T lymphocytes (CTLs). On the other hand, Th2 cells are involved in humoral immunity and suppressive to Th1 responses. Regulatory T (Treg) cells negatively regulate immune responses and contribute to immune evasion of tumor cells. Th17 cells are involved in inflammatory responses and may play a role in tumor progression. However, recent studies have also shown that Th17 cells are capable of directly inducting CTLs and thus may promote anti-tumor immunity. Besides these T cell subsets, there are many other innate immune cells such as dendritic cells (DCs), natural killer (NK) cells, and myeloid-derived suppressor cells (MDSCs) that are involved in host immune responses to cancer. The migratory properties of various immune cells are critical for their functions and largely regulated by the chemokine superfamily. Thus, chemokines and chemokine receptors play vital roles in the orchestration of host immune responses to cancer. In this review, we overview the various immune cells involved in host responses to cancer and their migratory properties regulated by the chemokine superfamily. Understanding the roles of chemokines and chemokine receptors in host immune responses to cancer may provide new therapeutic opportunities for cancer immunotherapy.

scholarly journals Cytokines mediated hyperinflammation in SARS-CoV2: An Overview

2020 ◽  
Vol 1 (supplement) ◽  
pp. 7
Author(s):  
Liaqat Ali
Keyword(s):  
Middle East ◽  
Severe Acute Respiratory Syndrome ◽  
Immune Responses ◽  
T Lymphocyte ◽  
Lymphoid Tissue ◽  
Inflammatory Responses ◽  
Cytokine Storm ◽  
Host Immune Responses ◽  
Lymphocyte Responses

Hyperinflammation induced by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV2) is a major cause of disease severity and mortality in infected patients. The immunopathogenesis of SARS-CoV2 infection is similar to the previous Middle East Respiratory Syndrome-related coronavirus (MERS-CoV) and SARS-CoV coronavirus with severe inflammatory responses. Therefore, severity of this viral infection is not only associated with the virus but also due to host immune responses. Hyperinflammatory responses due to cytokine storm are a centerpiece of SARS-CoV2 pathogenesis with overwhelming consequences for the host. Virus infected monocyte derived macrophages produce cytokines and this contributes to damage of lymphoid tissue and limits the lymphocyte responses. Blocking the deadly cytokine storm and T lymphocyte stimulation is a vital defense for treating SARS-CoV2. Here, we will describe the role of hyperinflamation and the involvement of cytokines in severe SARS-CoV2 infection.

scholarly journals DNA Methylation Modification Map to Predict Tumor Molecular Subtypes and Efficacy of Immunotherapy in Bladder Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Fangdie Ye ◽  
Yingchun Liang ◽  
Jimeng Hu ◽  
Yun Hu ◽  
Yufei Liu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bladder Cancer ◽  
Immune Responses ◽  
Clustering Algorithm ◽  
Molecular Subtypes ◽  
Methylation Status ◽  
Treatment Strategies ◽  
Global Dna Methylation ◽  
Immune Microenvironment ◽  
Underlying Mechanisms

Background: Considering the heterogeneity and complexity of epigenetic regulation in bladder cancer, the underlying mechanisms of global DNA methylation modification in the immune microenvironment must be investigated to predict the prognosis outcomes and clinical response to immunotherapy.Methods: We systematically assessed the DNA methylation modes of 985 integrated bladder cancer samples with the unsupervised clustering algorithm. Subsequently, these DNA methylation modes were analyzed for their correlations with features of the immune microenvironment. The principal analysis algorithm was performed to calculate the DMRscores of each samples for qualification analysis.Findings: Three DNA methylation modes were revealed among 985 bladder cancer samples, and these modes are related to diverse clinical outcomes and several immune microenvironment phenotypes, e.g., immune-desert, immune-inflamed, and immune-excluded ones. Then patients were classified into high- and low-DMRscore subgroups according to the DMRscore, which was calculated based on the expression of DNA methylation related genes (DMRGs). Patients with the low-DMRscore subgroup presented a prominent survival advantage that was significantly correlated to the immune-inflamed phenotype. Further analysis revealed that patients with low DMRscores exhibited less TP53 wild mutation, lower cancer stage and molecular subtypes were mainly papillary subtypes. In addition, an independent immunotherapy cohort confirmed that DMRscore could serve as a signature to predict prognosis outcomes and immune responses.Conclusion: Global DNA methylation modes can be used to predict the immunophenotypes, aggressiveness, and immune responses of bladder cancer. DNA methylation status assessments will strengthen our insights into the features of the immune microenvironment and promote the development of more effective treatment strategies.

scholarly journals Insights Into Host Cell Cytokines in Chlamydia Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenjing Xiang ◽  
Nanyan Yu ◽  
Aihua Lei ◽  
Xiaofang Li ◽  
Shui Tan ◽  
...  
Keyword(s):  
Immune Responses ◽  
Chlamydial Infection ◽  
Inflammatory Responses ◽  
Host Cells ◽  
Chlamydia Infection ◽  
Significant Morbidity ◽  
Host Immune Responses ◽  
Infection Biology ◽  
Severe Tissue ◽  
Host Tissues

Chlamydial infection causes a number of clinically relevant diseases and induces significant morbidity in humans. Immune and inflammatory responses contribute to both the clearance of Chlamydia infection and pathology in host tissues. Chlamydia infection stimulates host cells to produce a large number of cytokines that trigger and regulate host immune responses against Chlamydia. However, inappropriate responses can occur with excessive production of cytokines, resulting in overreactive inflammatory responses and alterations in host or Chlamydia metabolism. As a result, Chlamydia persists and causes wound healing delays, leading to more severe tissue damage and triggering long-lasting fibrotic sequelae. Here, we summarize the roles of cytokines in Chlamydia infection and pathogenesis, thus advancing our understanding chlamydial infection biology and the pathogenic mechanisms involved.

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