scholarly journals Complex responses to inflammatory oxidants by the probiotic bacterium Lactobacillus reuteri

2019 ◽  
Author(s):  
Poulami Basu Thakur ◽  
Abagail R. Long ◽  
Benjamin J. Nelson ◽  
Ranjit Kumar ◽  
Alexander F. Rosenberg ◽  
...  
Keyword(s):  
Immune System ◽  
Hypochlorous Acid ◽  
Lactobacillus Reuteri ◽  
Inflammatory Diseases ◽  
Small Heat Shock Protein ◽  
Probiotic Bacterium ◽  
Transcriptomic Response ◽  
E Coli ◽  
Anti Inflammatory ◽  
Associated Species

ABSTRACTInflammatory diseases of the gut are associated with increased intestinal oxygen concentrations and high levels of inflammatory oxidants, including hydrogen peroxide (H2O2) and hypochlorous acid (HOCl), which are antimicrobial compounds produced by the innate immune system. This contributes to dysbiotic changes in the gut microbiome, including increased populations of pro-inflammatory enterobacteria (Escherichia coli and related species) and decreased levels of health-associated anaerobic Firmicutes and Bacteroidetes. The pathways for H2O2 and HOCl resistance in E. coli have been well-studied, but little is known about how commensal and probiotic bacteria respond to inflammatory oxidants. In this work, we have characterized the transcriptomic response of the anti-inflammatory, gut-colonizing Gram-positive probiotic Lactobacillus reuteri to both H2O2 and HOCl. L. reuteri mounts distinct responses to each of these stressors, and both gene expression and survival were strongly affected by the presence or absence of oxygen. Oxidative stress response in L. reuteri required several factors not found in enterobacteria, including the small heat shock protein Lo18, polyphosphate kinase 2, and RsiR, an L. reuteri-specific regulator of anti-inflammatory mechanisms. These results raise the intriguing possibility of developing treatments for inflammatory gut diseases that could sensitize pro-inflammatory enterobacteria to killing by the immune system while sparing anti-inflammatory, health-associated species.IMPORTANCEIt is becoming increasingly clear that effective treatment of inflammatory gut diseases will require modulation of the gut microbiota. Preventing pro-inflammatory bacteria from blooming while also preserving anti-inflammatory and commensal species is a considerable challenge, but our results suggest that it may be possible to take advantage of differences in the way different species of gut bacteria resist inflammatory oxidants to accomplish this goal.

scholarly journals Complex Responses to Hydrogen Peroxide and Hypochlorous Acid by the Probiotic Bacterium Lactobacillus reuteri

mSystems ◽  
2019 ◽  
Vol 4 (5) ◽  
Author(s):  
Poulami Basu Thakur ◽  
Abagail R. Long ◽  
Benjamin J. Nelson ◽  
Ranjit Kumar ◽  
Alexander F. Rosenberg ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Immune System ◽  
Stress Response ◽  
Hypochlorous Acid ◽  
Lactobacillus Reuteri ◽  
Probiotic Bacterium ◽  
Antimicrobial Compounds ◽  
Transcriptomic Response ◽  
Content Type ◽  
Anti Inflammatory

ABSTRACT Inflammatory diseases of the gut are associated with increased intestinal oxygen concentrations and high levels of inflammatory oxidants, including hydrogen peroxide (H2O2) and hypochlorous acid (HOCl), which are antimicrobial compounds produced by the innate immune system. This contributes to dysbiotic changes in the gut microbiome, including increased populations of proinflammatory enterobacteria (Escherichia coli and related species) and decreased levels of health-associated anaerobic Firmicutes and Bacteroidetes. The pathways for H2O2 and HOCl resistance in E. coli have been well studied, but little is known about how commensal and probiotic bacteria respond to inflammatory oxidants. In this work, we have characterized the transcriptomic response of the anti-inflammatory, gut-colonizing Gram-positive probiotic Lactobacillus reuteri to both H2O2 and HOCl. L. reuteri mounts distinct but overlapping responses to each of these stressors, and both gene expression and survival were strongly affected by the presence or absence of oxygen. Oxidative stress response in L. reuteri required several factors not found in enterobacteria, including the small heat shock protein Lo18, polyphosphate kinase 2, and RsiR, an L. reuteri-specific regulator of anti-inflammatory mechanisms. IMPORTANCE Reactive oxidants, including hydrogen peroxide and hypochlorous acid, are antimicrobial compounds produced by the immune system during inflammation. Little is known, however, about how many important types of bacteria present in the human microbiome respond to these oxidants, especially commensal and other health-associated species. We have now mapped the stress response to both H2O2 and HOCl in the intestinal lactic acid bacterium Lactobacillus reuteri.

scholarly journals Modeling Inflammation in Zebrafish for the Development of Anti-inflammatory Drugs

2021 ◽  
Vol 8 ◽  
Author(s):  
Yufei Xie ◽  
Annemarie H. Meijer ◽  
Marcel J. M. Schaaf
Keyword(s):  
Immune System ◽  
Inflammatory Response ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Model Systems ◽  
Trinitrobenzene Sulfonic Acid ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

Dysregulation of the inflammatory response in humans can lead to various inflammatory diseases, like asthma and rheumatoid arthritis. The innate branch of the immune system, including macrophage and neutrophil functions, plays a critical role in all inflammatory diseases. This part of the immune system is well-conserved between humans and the zebrafish, which has emerged as a powerful animal model for inflammation, because it offers the possibility to image and study inflammatory responses in vivo at the early life stages. This review focuses on different inflammation models established in zebrafish, and how they are being used for the development of novel anti-inflammatory drugs. The most commonly used model is the tail fin amputation model, in which part of the tail fin of a zebrafish larva is clipped. This model has been used to study fundamental aspects of the inflammatory response, like the role of specific signaling pathways, the migration of leukocytes, and the interaction between different immune cells, and has also been used to screen libraries of natural compounds, approved drugs, and well-characterized pathway inhibitors. In other models the inflammation is induced by chemical treatment, such as lipopolysaccharide (LPS), leukotriene B4 (LTB4), and copper, and some chemical-induced models, such as treatment with trinitrobenzene sulfonic acid (TNBS), specifically model inflammation in the gastro-intestinal tract. Two mutant zebrafish lines, carrying a mutation in the hepatocyte growth factor activator inhibitor 1a gene (hai1a) and the cdp-diacylglycerolinositol 3-phosphatidyltransferase (cdipt) gene, show an inflammatory phenotype, and they provide interesting model systems for studying inflammation. These zebrafish inflammation models are often used to study the anti-inflammatory effects of glucocorticoids, to increase our understanding of the mechanism of action of this class of drugs and to develop novel glucocorticoid drugs. In this review, an overview is provided of the available inflammation models in zebrafish, and how they are used to unravel molecular mechanisms underlying the inflammatory response and to screen for novel anti-inflammatory drugs.

scholarly journals Neutrophil Myeloperoxidase Derived Chlorolipid Production During Bacteria Exposure

2021 ◽  
Vol 12 ◽  
Author(s):  
Kaushalya Amunugama ◽  
Grant R. Kolar ◽  
David A. Ford
Keyword(s):  
Hypochlorous Acid ◽  
Inflammatory Diseases ◽  
White Blood Cells ◽  
Neutrophil Extracellular Trap ◽  
Neutrophil Chemotaxis ◽  
Bacterial Killing ◽  
E Coli ◽  
Infection And Inflammation ◽  
Strain Cft073 ◽  
Different Strains

Neutrophils are the most abundant white blood cells recruited to the sites of infection and inflammation. During neutrophil activation, myeloperoxidase (MPO) is released and converts hydrogen peroxide to hypochlorous acid (HOCl). HOCl reacts with plasmalogen phospholipids to liberate 2-chlorofatty aldehyde (2-ClFALD), which is metabolized to 2-chlorofatty acid (2-ClFA). 2-ClFA and 2-ClFALD are linked with inflammatory diseases and induce endothelial dysfunction, neutrophil extracellular trap formation (NETosis) and neutrophil chemotaxis. Here we examine the neutrophil-derived chlorolipid production in the presence of pathogenic E. coli strain CFT073 and non-pathogenic E. coli strain JM109. Neutrophils cocultured with CFT073 E. coli strain and JM109 E. coli strain resulted in 2-ClFALD production. 2-ClFA was elevated only in CFT073 coculture. NETosis is more prevalent in CFT073 cocultures with neutrophils compared to JM109 cocultures. 2-ClFA and 2-ClFALD were both shown to have significant bactericidal activity, which is more severe in JM109 E. coli. 2-ClFALD metabolic capacity was 1000-fold greater in neutrophils compared to either strain of E. coli. MPO inhibition reduced chlorolipid production as well as bacterial killing capacity. These findings indicate the chlorolipid profile is different in response to these two different strains of E. coli bacteria.

scholarly journals Immunomodulatory Role of Nutrients: How Can Pulmonary Dysfunctions Improve?

2021 ◽  
Vol 8 ◽  
Author(s):  
Sarah Cristina Gozzi-Silva ◽  
Franciane Mouradian Emidio Teixeira ◽  
Alberto José da Silva Duarte ◽  
Maria Notomi Sato ◽  
Luana de Mendonça Oliveira
Keyword(s):  
Fatty Acids ◽  
Immune Response ◽  
Immune System ◽  
Viral Infections ◽  
Inflammatory Diseases ◽  
Dietary Factors ◽  
Chronic Inflammatory Diseases ◽  
Anti Inflammatory ◽  
Lung Health

Nutrition is an important tool that can be used to modulate the immune response during infectious diseases. In addition, through diet, important substrates are acquired for the biosynthesis of regulatory molecules in the immune response, influencing the progression and treatment of chronic lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD). In this way, nutrition can promote lung health status. A range of nutrients, such as vitamins (A, C, D, and E), minerals (zinc, selenium, iron, and magnesium), flavonoids and fatty acids, play important roles in reducing the risk of pulmonary chronic diseases and viral infections. Through their antioxidant and anti-inflammatory effects, nutrients are associated with better lung function and a lower risk of complications since they can decrease the harmful effects from the immune system during the inflammatory response. In addition, bioactive compounds can even contribute to epigenetic changes, including histone deacetylase (HDAC) modifications that inhibit the transcription of proinflammatory cytokines, which can contribute to the maintenance of homeostasis in the context of infections and chronic inflammatory diseases. These nutrients also play an important role in activating immune responses against pathogens, which can help the immune system during infections. Here, we provide an updated overview of the roles played by dietary factors and how they can affect respiratory health. Therefore, we will show the anti-inflammatory role of flavonoids, fatty acids, vitamins and microbiota, important for the control of chronic inflammatory diseases and allergies, in addition to the antiviral role of vitamins, flavonoids, and minerals during pulmonary viral infections, addressing the mechanisms involved in each function. These mechanisms are interesting in the discussion of perspectives associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its pulmonary complications since patients with severe disease have vitamins deficiency, especially vitamin D. In addition, researches with the use of flavonoids have been shown to decrease viral replication in vitro. This way, a full understanding of dietary influences can improve the lung health of patients.

scholarly journals Caffeic Acid Phenethyl Ester: Consequences of Its Hydrophobicity in the Oxidative Functions and Cytokine Release by Leukocytes

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Luana Chiquetto Paracatu ◽  
Carolina Maria Quinello Gomes Faria ◽  
Camila Quinello ◽  
Camila Rennó ◽  
Patricia Palmeira ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Caffeic Acid ◽  
Superoxide Anion ◽  
Hypochlorous Acid ◽  
Inflammatory Diseases ◽  
Biological Effects ◽  
Caffeic Acid Phenethyl Ester ◽  
Nadph Oxidases ◽  
Tnf Α ◽  
Anti Inflammatory

Numerous anti-inflammatory properties have been attributed to caffeic acid phenethyl ester (CAPE), an active component of propolis. NADPH oxidases are multienzymatic complexes involved in many inflammatory diseases. Here, we studied the importance of the CAPE hydrophobicity on cell-free antioxidant capacity, inhibition of the NADPH oxidase and hypochlorous acid production, and release of TNF-α and IL-10 by activated leukocytes. The comparison was made with the related, but less hydrophobic, caffeic and chlorogenic acids. Cell-free studies such as superoxide anion scavenging assay, triene degradation, and anodic peak potential(Epa)measurements showed that the alterations in the hydrophobicity did not provoke significant changes in the oxidation potential and antiradical potency of the tested compounds. However, only CAPE was able to inhibit the production of superoxide anion by activated leukocytes. The inhibition of the NADPH oxidase resulted in the blockage of production of hypochlorous acid. Similarly, CAPE was the more effective inhibitor of the release of TNF-α and IL-10 byStaphylococcus aureusstimulated cells. In conclusion, the presence of the catechol moiety and the higher hydrophobicity were essential for the biological effects. Considering the involvement of NADPH oxidases in the genesis and progression of inflammatory diseases, CAPE should be considered as a promising anti-inflammatory drug.

scholarly journals The Role of the Immune System in IBD-Associated Colorectal Cancer: From Pro to Anti-Tumorigenic Mechanisms

2021 ◽  
Vol 22 (23) ◽  
pp. 12739
Author(s):  
Sofía Frigerio ◽  
Dalia A. Lartey ◽  
Geert R. D’Haens ◽  
Joep Grootjans
Keyword(s):  
Colorectal Cancer ◽  
Immune System ◽  
Chronic Inflammation ◽  
Immune Cells ◽  
Checkpoint Inhibitors ◽  
Inflammatory Diseases ◽  
Cancer Development ◽  
Anti Inflammatory ◽  
Immunosuppressive Microenvironment

Patients with inflammatory bowel disease (IBD) have increased incidence of colorectal cancer (CRC). IBD-associated cancer follows a well-characterized sequence of intestinal epithelial changes, in which genetic mutations and molecular aberrations play a key role. IBD-associated cancer develops against a background of chronic inflammation and pro-inflammatory immune cells, and their products contribute to cancer development and progression. In recent years, the effect of the immunosuppressive microenvironment in cancer development and progression has gained more attention, mainly because of the unprecedented anti-tumor effects of immune checkpoint inhibitors in selected groups of patients. Even though IBD-associated cancer develops in the background of chronic inflammation which is associated with activation of endogenous anti-inflammatory or suppressive mechanisms, the potential role of an immunosuppressive microenvironment in these cancers is largely unknown. In this review, we outline the role of the immune system in promoting cancer development in chronic inflammatory diseases such as IBD, with a specific focus on the anti-inflammatory mechanisms and suppressive immune cells that may play a role in IBD-associated tumorigenesis.

Sulphonamides as Anti-Inflammatory Agents: Old Drugs for New Therapeutic Strategies in Neutrophilic Inflammation?

1995 ◽  
Vol 88 (3) ◽  
pp. 331-336 ◽  
Author(s):  
Luciano Ottonello ◽  
Patrizia Dapino ◽  
Maria C. Scirocco ◽  
Alessandro Balbi ◽  
Maurizio Bevilacqua ◽  
...  
Keyword(s):  
Hypochlorous Acid ◽  
Tissue Injury ◽  
Inflammatory Diseases ◽  
Specific Inhibitor ◽  
Therapeutic Strategies ◽  
Dependent Manner ◽  
Neutrophilic Inflammation ◽  
Starting Point ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

1. It is well known that neutrophils act as mediators of tissue injury in a variety of inflammatory diseases. Their histotoxic activity is presently thought to involve proteinases and oxidants, primarily hypochlorous acid (HOCl). This oxidant is also capable of inactivating the specific inhibitor of neutrophil elastase (α1-antitrypsin), thereby favouring digestion of the connective matrix. 2. In the present work, we found that sulphanilamide and some sulphanilamide-related anti-inflammatory drugs such as dapsone, nimesulide and sulphapyridine reduce the availability of HOCl in the extracellular microenvironment of activated neutrophils and prevent the inactivation of α1-antitrypsin by these cells in a dose-dependent manner. The ability of each drug to prevent α1-antitrypsin from inactivation by neutrophils correlates significantly with its capacity to reduce the recovery of HOCl from neutrophils. Five other non-steroidal anti-inflammatory drugs were completely ineffective. 3. Therefore, sulphanilamide-related drugs, i.e. dapsone, nimesulide and sulphapyridine, have the potential to reduce the bioavailability of neutrophil-derived HOCl and, in turn, to favour the α1-antitrypsin-dependent control of neutrophil elastolytic activity. These drugs appear as a well-defined group of agents which are particularly prone to attenuate neutrophil histotoxicity. They can also be viewed as a previously unrecognized starting point for the development of new compounds in order to plan rational therapeutic strategies for controlling tissue injury during neutrophilic inflammation.

scholarly journals Interactions between the Parasite Philasterides dicentrarchi and the Immune System of the Turbot Scophthalmus maximus. A Transcriptomic Analysis

Biology ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 337
Author(s):  
Alejandra Valle ◽  
José Manuel Leiro ◽  
Patricia Pereiro ◽  
Antonio Figueras ◽  
Beatriz Novoa ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Scophthalmus Maximus ◽  
Signalling Pathway ◽  
Transcriptomic Analysis ◽  
Host Immune System ◽  
Transcriptomic Response ◽  
Peritoneal Cells ◽  
Anti Inflammatory ◽  
Turbot Scophthalmus Maximus

The present study analyses the interactions between Philasterides dicentrarchi (a ciliate parasite that causes high mortalities in cultured flatfish) and the peritoneal cells of the turbot Scophthalmus maximus during an experimental infection. The transcriptomic response was evaluated in the parasites and in the fish peritoneal cells, at 1, 2 and 4 h post-infection (hpi) in turbot injected intraperitoneally (ip) with 107 ciliates and at 12 and 48 hpi in turbot injected ip with 105 ciliates. Numerous genes were differentially expressed (DE) in P. dicentrarchi, relative to their expression in control ciliates (0 hpi): 407 (369 were up-regulated) at 1 hpi, 769 (415 were up-regulated) at 2 hpi and 507 (119 were up-regulated) at 4 hpi. Gene ontology (GO) analysis of the DE genes showed that the most representative categories of biological processes affected at 1, 2 and 4 hpi were biosynthetic processes, catabolic processes, biogenesis, proteolysis and transmembrane transport. Twelve genes of the ABC transporter family and eight genes of the leishmanolysin family were DE at 1, 2 and 4 hpi. Most of these genes were strongly up-regulated (UR), suggesting that they are involved in P. dicentrarchi infection. A third group of UR genes included several genes related to ribosome biogenesis, DNA transcription and RNA translation. However, expression of tubulins and tubulin associated proteins, such as kinesins or dyneins, which play key roles in ciliate division and movement, was down-regulated (DR). Similarly, genes that coded for lysosomal proteins or that participate in the cell cycle mitotic control, glycolysis, the Krebs cycle and/or in the electron transport chain were also DR. The transcriptomic analysis also revealed that in contrast to many parasites, which passively evade the host immune system, P. dicentrarchi strongly stimulated turbot peritoneal cells. Many genes related to inflammation were DE in peritoneal cells at 1, 2 and 4 hpi. However, the response was much lower at 12 hpi and almost disappeared completely at 48 hpi in fish that were able to kill P. dicentrarchi during the first few hpi. The genes that were DE at 1, 2 and 4 hpi were mainly related to the apoptotic process, the immune response, the Fc-epsilon receptor signalling pathway, the innate immune response, cell adhesion, cell surface receptors, the NF-kappaB signalling pathway and the MAPK cascade. Expression of toll-like receptors 2, 5 and 13 and of several components of NF-κB, MAPK and JAK/STAT signalling pathways was UR in the turbot peritoneal cells. Genes expressing chemokines and chemokine receptors, genes involved in prostaglandin and leukotriene synthesis, prostaglandins, leukotriene receptors, proinflammatory cytokines and genes involved in apoptosis were strongly UR during the first four hours of infection. However, expression of anti-inflammatory cytokines such as Il-10 and lipoxygenases with anti-inflammatory activity (i.e., arachidonate 15-lipoxygenase) were only UR at 12 and/or 48 hpi, indicating an anti-inflammatory state in these groups of fish. In conclusion, the present study shows the regulation of several genes in P. dicentrarchi during the early stages of infection, some of which probably play important roles in this process. The infection induced a potent acute inflammatory response, and many inflammatory genes were regulated in peritoneal cells, showing that the turbot uses all the protective mechanisms it has available to prevent the entry of the parasite.

scholarly journals The Cu(II) Reductase RclA Protects Escherichia coli against the Combination of Hypochlorous Acid and Intracellular Copper

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Rhea M. Derke ◽  
Alexander J. Barron ◽  
Caitlin E. Billiot ◽  
Ivis F. Chaple ◽  
Suzanne E. Lapi ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Immune System ◽  
Innate Immune System ◽  
Hypochlorous Acid ◽  
Innate Immune ◽  
Antimicrobial Compounds ◽  
Content Type ◽  
Animal Host ◽  
E Coli ◽  
Intracellular Copper

ABSTRACT Enterobacteria, including Escherichia coli, bloom to high levels in the gut during inflammation and strongly contribute to the pathology of inflammatory bowel diseases. To survive in the inflamed gut, E. coli must tolerate high levels of antimicrobial compounds produced by the immune system, including toxic metals like copper and reactive chlorine oxidants such as hypochlorous acid (HOCl). Here, we show that extracellular copper is a potent detoxifier of HOCl and that the widely conserved bacterial HOCl resistance enzyme RclA, which catalyzes the reduction of copper(II) to copper(I), specifically protects E. coli against damage caused by the combination of HOCl and intracellular copper. E. coli lacking RclA was highly sensitive to HOCl when grown in the presence of copper and was defective in colonizing an animal host. Our results indicate that there is unexpected complexity in the interactions between antimicrobial toxins produced by innate immune cells and that bacterial copper status is a key determinant of HOCl resistance and suggest an important and previously unsuspected role for copper redox reactions during inflammation. IMPORTANCE During infection and inflammation, the innate immune system uses antimicrobial compounds to control bacterial populations. These include toxic metals, like copper, and reactive oxidants, including hypochlorous acid (HOCl). We have now found that RclA, a copper(II) reductase strongly induced by HOCl in proinflammatory Escherichia coli and found in many bacteria inhabiting epithelial surfaces, is required for bacteria to resist killing by the combination of intracellular copper and HOCl and plays an important role in colonization of an animal host. This finding indicates that copper redox chemistry plays a critical and previously underappreciated role in bacterial interactions with the innate immune system.

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