scholarly journals Gut SymbiontsLactobacillus reuteriR2lc and 2010 Encode a Polyketide Synthase Cluster That Activates the Mammalian Aryl Hydrocarbon Receptor

2018 ◽  
Vol 85 (10) ◽  
Author(s):  
Mustafa Özçam ◽  
Restituto Tocmo ◽  
Jee-Hwan Oh ◽  
Amin Afrazi ◽  
Joshua D. Mezrich ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Immune System ◽  
Aryl Hydrocarbon Receptor ◽  
Gene Cluster ◽  
Polyketide Synthase ◽  
Lactobacillus Reuteri ◽  
Intestinal Inflammation ◽  
Host Immune System ◽  
Content Type ◽  
Aryl Hydrocarbon

ABSTRACTA mechanistic understanding of microbe-host interactions is critical to developing therapeutic strategies for targeted modulation of the host immune system. Different members of the gut symbiont speciesLactobacillus reuterimodulate host health by, for example, reduction of intestinal inflammation. Previously, it was shown thatL. reuteriactivates the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that plays an important role in the mucosal immune system, by the production of tryptophan catabolites. Here, we identified a novel pathway by whichL. reuteriactivates AhR, which is independent of tryptophan metabolism. We screened a library of 36 L. reuteristrains and determined that R2lc and 2010, strains with a pigmented phenotype, are potent AhR activators. By whole-genome sequencing and comparative genomics, we identified genes unique to R2lc and 2010. Our analyses demonstrated that R2lc harbors two genetically distinct polyketide synthase (PKS) clusters, functionally unknown (fun) andpks, each carried by a multicopy plasmid. Inactivation ofpks, but notfun, abolished the ability of R2lc to activate AhR.L. reuteri2010 has a gene cluster homologous to thepkscluster in R2lc with an identical gene organization, which is also responsible for AhR activation. In conclusion, we identified a novel PKS pathway inL. reuteriR2lc and 2010 that is responsible for AhR activation.IMPORTANCETemporary changes in the composition of the microbiota, for example, by oral administration of probiotics, can modulate the host immune system. However, the underlying mechanisms by which probiotics interact with the host are often unknown. Here, we show thatLactobacillus reuteriR2lc and 2010 harbor an orthologous PKS gene cluster that activates the aryl hydrocarbon receptor (AhR). AhR is a ligand-activated transcription factor that plays a key role in a variety of diseases, including amelioration of intestinal inflammation. Understanding the mechanism by which a bacterium modulates the immune system is critical for applying rational selection strategies for probiotic supplementation. Finally, heterologous and/or optimized expression of PKS is a logical next step toward the development of next-generation probiotics to prevent and treat disease.

scholarly journals Does NLRP3 Inflammasome and Aryl Hydrocarbon Receptor Play an Interlinked Role in Bowel Inflammation and Colitis-Associated Colorectal Cancer?

Molecules ◽  
2020 ◽  
Vol 25 (10) ◽  
pp. 2427
Author(s):  
Ivan Qi Han Ngui ◽  
Agampodi Promoda Perera ◽  
Rajaraman Eri
Keyword(s):  
Colorectal Cancer ◽  
Immune System ◽  
Aryl Hydrocarbon Receptor ◽  
Nlrp3 Inflammasome ◽  
Intestinal Inflammation ◽  
Strong Association ◽  
Signalling Pathways ◽  
Inflammasome Activation ◽  
Intestinal Immunity ◽  
Aryl Hydrocarbon

Inflammation is a hallmark in many forms of cancer; with colitis-associated colorectal cancer (CAC) being a progressive intestinal inflammation due to inflammatory bowel disease (IBD). While this is an exemplification of the negatives of inflammation, it is just as crucial to have some degree of the inflammatory process to maintain a healthy immune system. A pivotal component in the maintenance of such intestinal homeostasis is the innate immunity component, inflammasomes. Inflammasomes are large, cytosolic protein complexes formed following stimulation of microbial and stress signals that lead to the expression of pro-inflammatory cytokines. The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome has been extensively studied in part due to its strong association with colitis and CAC. The aryl hydrocarbon receptor (AhR) has recently been acknowledged for its connection to the immune system aside from its role as an environmental sensor. AhR has been described to play a role in the inhibition of the NLRP3 inflammasome activation pathway. This review will summarise the signalling pathways of both the NLRP3 inflammasome and AhR; as well as new-found links between these two signalling pathways in intestinal immunity and some potential therapeutic agents that have been found to take advantage of this link in the treatment of colitis and CAC.

scholarly journals Trajectory Shifts in Interdisciplinary Research of the Aryl Hydrocarbon Receptor—A Personal Perspective on Thymus and Skin

2021 ◽  
Vol 22 (4) ◽  
pp. 1844
Author(s):  
Charlotte Esser
Keyword(s):  
Transcription Factor ◽  
Immune System ◽  
Environmental Pollution ◽  
Aryl Hydrocarbon Receptor ◽  
Interdisciplinary Research ◽  
Adaptive Response ◽  
Personal Perspective ◽  
Aryl Hydrocarbon

Identifying historical trajectories is a useful exercise in research, as it helps clarify important, perhaps even “paradigmatic”, shifts in thinking and moving forward in science. In this review, the development of research regarding the role of the transcription factor “aryl hydrocarbon receptor” (AHR) as a mediator of the toxicity of environmental pollution towards a link between the environment and a healthy adaptive response of the immune system and the skin is discussed. From this fascinating development, the opportunities for targeting the AHR in the therapy of many diseases become clear.

scholarly journals Cryptococcus neoformans Rim101 Is Associated with Cell Wall Remodeling and Evasion of the Host Immune Responses

mBio ◽  
2013 ◽  
Vol 4 (1) ◽  
Author(s):  
Teresa R. O'Meara ◽  
Stephanie M. Holmer ◽  
Kyla Selvig ◽  
Fred Dietrich ◽  
J. Andrew Alspaugh
Keyword(s):  
Immune Response ◽  
Cell Wall ◽  
Transcription Factor ◽  
Immune System ◽  
Immune Responses ◽  
Cryptococcus Neoformans ◽  
Host Immune Response ◽  
Host Immune System ◽  
Content Type ◽  
Host Pathogen

ABSTRACTInfectious microorganisms often play a role in modulating the immune responses of their infected hosts. We demonstrate thatCryptococcus neoformanssignals through the Rim101 transcription factor to regulate cell wall composition and the host-pathogen interface. In the absence of Rim101,C. neoformansexhibits an altered cell surface in response to host signals, generating an excessive and ineffective immune response that results in accelerated host death. This host immune response to therim101Δ mutant strain is characterized by increased neutrophil influx into the infected lungs and an altered pattern of host cytokine expression compared to the response to wild-type cryptococcal infection. To identify genes associated with the observed phenotypes, we performed whole-genome RNA sequencing experiments under capsule-inducing conditions. We defined the downstream regulon of the Rim101 transcription factor and determined potential cell wall processes involved in the capsule attachment defects and altered mechanisms of virulence in therim101Δ mutant. The cell wall generates structural stability for the cell and allows the attachment of surface molecules such as capsule polysaccharides. In turn, the capsule provides an effective mask for the immunogenic cell wall, shielding it from recognition by the host immune system.IMPORTANCECryptococcus neoformansis an opportunistic human pathogen that is a significant cause of death in immunocompromised individuals. There are two major causes of death due to this pathogen: meningitis due to uncontrolled fungal proliferation in the brain in the face of a weakened immune system and immune reconstitution inflammatory syndrome characterized by an overactive immune response to subclinical levels of the pathogen. In this study, we examined howC. neoformansuses the conserved Rim101 transcription factor to specifically remodel the host-pathogen interface, thus regulating the host immune response. These studies explored the complex ways in which successful microbial pathogens induce phenotypes that ensure their own survival while simultaneously controlling the nature and degree of the associated host response.

scholarly journals Aryl Hydrocarbon Receptor Connects Inflammation to Breast Cancer

2020 ◽  
Vol 21 (15) ◽  
pp. 5264 ◽  
Author(s):  
Tiziana Guarnieri
Keyword(s):  
Breast Cancer ◽  
Transcription Factor ◽  
Immune System ◽  
Aryl Hydrocarbon Receptor ◽  
Inflammatory Marker ◽  
Eukaryotic Cells ◽  
Breast Carcinogenesis ◽  
Constitutive Activation ◽  
Aryl Hydrocarbon ◽  
Over Time

Aryl hydrocarbon receptor (AhR), an evolutionary conserved transcription factor, is a pleiotropic signal transductor. Thanks to its promiscuous ligand binding domain, during the evolution of eukaryotic cells its developmental functions were integrated with biosensor functions. Its activation by a multitude of endogenous and exogenous molecules stimulates its participation in several pathways, some of which are linked to inflammation and breast cancer (BC). Over time, the study of this malignancy has led to the identification of several therapeutic targets in cancer cells. An intense area of study is dedicated to BC phenotypes lacking adequate targets. In this context, due to its high constitutive activation in BC, AhR is currently gaining more and more attention. In this review, I have considered its interactions with: 1. the immune system, whose dysregulation is a renowned cancer hallmark; 2. interleukin 6 (IL6) which is a pivotal inflammatory marker and is closely correlated to breast cancer risk; 3. NF-kB, another evolutionary conserved transcription factor, which plays a key role in immunoregulatory functions, inflammatory response and breast carcinogenesis; 4. kynurenine, a tryptophan-derived ligand that activates and bridges AhR to chronic inflammation and breast carcinogenesis. Overall, the data here presented form an interesting framework where AhR is an interesting connector between inflammation and BC.

scholarly journals Immunotoxicity of Xenobiotics in Fish: A Role for the Aryl Hydrocarbon Receptor (AhR)?

2021 ◽  
Vol 22 (17) ◽  
pp. 9460
Author(s):  
Helmut Segner ◽  
Christyn Bailey ◽  
Carolina Tafalla ◽  
Jun Bo
Keyword(s):  
Immune System ◽  
Aryl Hydrocarbon Receptor ◽  
Disease Susceptibility ◽  
Immune Cell ◽  
Physiological Role ◽  
Immune Gene ◽  
Immune Systems ◽  
Aryl Hydrocarbon ◽  
The Impact

The impact of anthropogenic contaminants on the immune system of fishes is an issue of growing concern. An important xenobiotic receptor that mediates effects of chemicals, such as halogenated aromatic hydrocarbons (HAHs) and polyaromatic hydrocarbons (PAHs), is the aryl hydrocarbon receptor (AhR). Fish toxicological research has focused on the role of this receptor in xenobiotic biotransformation as well as in causing developmental, cardiac, and reproductive toxicity. However, biomedical research has unraveled an important physiological role of the AhR in the immune system, what suggests that this receptor could be involved in immunotoxic effects of environmental contaminants. The aims of the present review are to critically discuss the available knowledge on (i) the expression and possible function of the AhR in the immune systems of teleost fishes; and (ii) the impact of AhR-activating xenobiotics on the immune systems of fish at the levels of immune gene expression, immune cell proliferation and immune cell function, immune pathology, and resistance to infectious disease. The existing information indicates that the AhR is expressed in the fish immune system, but currently, we have little understanding of its physiological role. Exposure to AhR-activating contaminants results in the modulation of numerous immune structural and functional parameters of fish. Despite the diversity of fish species studied and the experimental conditions investigated, the published findings rather uniformly point to immunosuppressive actions of xenobiotic AhR ligands in fish. These effects are often associated with increased disease susceptibility. The fact that fish populations from HAH- and PAH-contaminated environments suffer immune disturbances and elevated disease susceptibility highlights that the immunotoxic effects of AhR-activating xenobiotics bear environmental relevance.

Polycyclic Aromatic Hydrocarbons Can Trigger Hepatocyte Release of Extracellular Vesicles by Various Mechanisms of Action Depending on Their Affinity for the Aryl Hydrocarbon Receptor

2019 ◽  
Vol 171 (2) ◽  
pp. 443-462 ◽  
Author(s):  
Nettie van Meteren ◽  
Dominique Lagadic-Gossmann ◽  
Martine Chevanne ◽  
Isabelle Gallais ◽  
Dimitri Gobart ◽  
...  
Keyword(s):  
Cell Death ◽  
Transcription Factor ◽  
Polycyclic Aromatic Hydrocarbons ◽  
Cell Membrane ◽  
Aryl Hydrocarbon Receptor ◽  
Extracellular Vesicles ◽  
Aromatic Hydrocarbons ◽  
Aryl Hydrocarbon ◽  
Polycyclic Aromatic ◽  
Cell Membrane Fluidity

Abstract Extracellular vesicles (EVs) are membrane-enclosed nanostructures released by cells into the extracellular environment. As major actors of physiological intercellular communication, they have been shown to be pathogenic mediators of several liver diseases. Extracellular vesicles also appear to be potential actors of drug-induced liver injury but nothing is known concerning environmental pollutants. We aimed to study the impact of polycyclic aromatic hydrocarbons (PAHs), major contaminants, on hepatocyte-derived EV production, with a special focus on hepatocyte death. Three PAHs were selected, based on their presence in food and their affinity for the aryl hydrocarbon receptor (AhR): benzo[a]pyrene (BP), dibenzo[a,h]anthracene (DBA), and pyrene (PYR). Treatment of primary rat and WIF-B9 hepatocytes by all 3 PAHs increased the release of EVs, mainly comprised of exosomes, in parallel with modifying exosome protein marker expression and inducing apoptosis. Moreover, PAH treatment of rodents for 3 months also led to increased EV levels in plasma. The EV release involved CYP metabolism and the activation of the transcription factor, the AhR, for BP and DBA and another transcription factor, the constitutive androstane receptor, for PYR. Furthermore, all PAHs increased cholesterol levels in EVs but only BP and DBA were able to reduce the cholesterol content of total cell membranes. All cholesterol changes very likely participated in the increase in EV release and cell death. Finally, we studied changes in cell membrane fluidity caused by BP and DBA due to cholesterol depletion. Our data showed increased cell membrane fluidity, which contributed to hepatocyte EV release and cell death.

scholarly journals Selected Immunological Mediators and Cervical Microbial Signatures in Women with Chlamydia trachomatis Infection

mSystems ◽  
2019 ◽  
Vol 4 (4) ◽  
Author(s):  
Simone Filardo ◽  
Marisa Di Pietro ◽  
Giulia Tranquilli ◽  
Maria Agnese Latino ◽  
Nadia Recine ◽  
...  
Keyword(s):  
Immune System ◽  
Chlamydia Trachomatis ◽  
Host Immune System ◽  
Complex Interplay ◽  
Content Type ◽  
Immune Mediators ◽  
Potential Biomarker ◽  
Ifn Γ ◽  
Low Levels ◽  
Female Genital

ABSTRACT In the female genital ecosystem, the complex interplay between the host immune system and the resident microflora protects against urogenital pathogens, like Chlamydia trachomatis. C. trachomatis is responsible for urethritis and cervicitis; however, most chlamydial infections are asymptomatic and, thus, not treated, potentially leading to severe reproductive sequelae. Here we investigated the interaction between the levels of selected immune mediators and the community state types of the cervical microbiota in C. trachomatis-infected women. Cervical samples from 42 C. trachomatis-positive women and 103 matched healthy controls were analyzed through the metagenomic analysis of the hypervariable region v4 of the 16S rRNA gene and the determination of lactoferrin, interleukin 1α (IL-1α), IL-6, alpha interferon (IFN-α), IFN-β, and IFN-γ by ELISA. Overall, C. trachomatis infection was significantly associated with a microbiota dominated by anaerobic bacteria (P = 0.000002). In addition, a network of Gardnerella vaginalis, Prevotella amnii, Prevotella buccalis, Prevotella timonensis, Aerococcus christensenii, and Variovorax guangxiensis has been identified as a potential biomarker of C. trachomatis infection through multiple statistical approaches. Again, chlamydial infection was significantly correlated with an increased production of lactoferrin, IL-6, IL-1α, IFN-α, and IFN-β (P < 0.05), whereas very low levels of IFN-γ were observed in C. trachomatis-infected women, levels similar to those detected in healthy women. Our findings show a distinctive signature of C. trachomatis genital infection, characterized by a specific bacterial network, constituted by anaerobes, as well as by increased levels of lactoferrin and proinflammatory cytokines (IL-1α, IL-6, IFN-α, and IFN-β), accompanied by low levels of IFN-γ. IMPORTANCE To our knowledge, this is the first study that investigated the association of C. trachomatis with the cervical levels of lactoferrin and selected inflammatory mediators and their correlation with the different community state types characterizing the female genital ecosystem. C. trachomatis, known as the leading cause of bacterial sexually transmitted diseases, continues to be an important public health problem worldwide for its increasing incidence and the risk of developing severe reproductive sequelae, like pelvic inflammatory disease and infertility. Specifically, C. trachomatis tend to persist in the female genital tract, leading to a chronic inflammatory state characterized by increased production of immune mediators responsible for tissue damage. Therefore, our study may help to broaden the knowledge on the complex interplay between the female genital microbiota and the host immune system in response to C. trachomatis infection.

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