scholarly journals Tryptophan Metabolites and Aryl Hydrocarbon Receptor in Severe Acute Respiratory Syndrome, Coronavirus-2 (SARS-CoV-2) Pathophysiology

2021 ◽  
Vol 22 (4) ◽  
pp. 1597
Author(s):  
George Anderson ◽  
Annalucia Carbone ◽  
Gianluigi Mazzoccoli
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Immune Responses ◽  
Aryl Hydrocarbon Receptor ◽  
Epigallocatechin Gallate ◽  
Future Research ◽  
Elderly Age ◽  
Pineal Melatonin ◽  
Aryl Hydrocarbon ◽  
Obesity And Diabetes ◽  
Increased Risk

The metabolism of tryptophan is intimately associated with the differential regulation of diverse physiological processes, including in the regulation of responses to severe acute respiratory syndrome, coronavirus-2 (SARS-CoV-2) infection that underpins the COVID-19 pandemic. Two important products of tryptophan metabolism, viz kynurenine and interleukin (IL)4-inducible1 (IL41)-driven indole 3 pyruvate (I3P), activate the aryl hydrocarbon receptor (AhR), thereby altering the nature of immune responses to SARS-CoV-2 infection. AhR activation dysregulates the initial pro-inflammatory cytokines production driven by neutrophils, macrophages, and mast cells, whilst AhR activation suppresses the endogenous antiviral responses of natural killer cells and CD8+ T cells. Such immune responses become further dysregulated by the increased and prolonged pro-inflammatory cytokine suppression of pineal melatonin production coupled to increased gut dysbiosis and gut permeability. The suppression of pineal melatonin and gut microbiome-derived butyrate, coupled to an increase in circulating lipopolysaccharide (LPS) further dysregulates the immune response. The AhR mediates its effects via alterations in the regulation of mitochondrial function in immune cells. The increased risk of severe/fatal SARS-CoV-2 infection by high risk conditions, such as elderly age, obesity, and diabetes are mediated by these conditions having expression levels of melatonin, AhR, butyrate, and LPS that are closer to those driven by SARS-CoV-2 infection. This has a number of future research and treatment implications, including the utilization of melatonin and nutraceuticals that inhibit the AhR, including the polyphenols, epigallocatechin gallate (EGCG), and resveratrol.

scholarly journals Tumour Microenvironment: Roles of the Aryl Hydrocarbon Receptor, O-GlcNAcylation, Acetyl-CoA and Melatonergic Pathway in Regulating Dynamic Metabolic Interactions across Cell Types—Tumour Microenvironment and Metabolism

2020 ◽  
Vol 22 (1) ◽  
pp. 141
Author(s):  
George Anderson
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Glycogen Synthase ◽  
Tumour Progression ◽  
Cell Types ◽  
Tumour Microenvironment ◽  
Future Research ◽  
Acetyl Coa ◽  
Dynamic Interactions ◽  
Aryl Hydrocarbon ◽  
Metabolic Interactions

This article reviews the dynamic interactions of the tumour microenvironment, highlighting the roles of acetyl-CoA and melatonergic pathway regulation in determining the interactions between oxidative phosphorylation (OXPHOS) and glycolysis across the array of cells forming the tumour microenvironment. Many of the factors associated with tumour progression and immune resistance, such as yin yang (YY)1 and glycogen synthase kinase (GSK)3β, regulate acetyl-CoA and the melatonergic pathway, thereby having significant impacts on the dynamic interactions of the different types of cells present in the tumour microenvironment. The association of the aryl hydrocarbon receptor (AhR) with immune suppression in the tumour microenvironment may be mediated by the AhR-induced cytochrome P450 (CYP)1b1-driven ‘backward’ conversion of melatonin to its immediate precursor N-acetylserotonin (NAS). NAS within tumours and released from tumour microenvironment cells activates the brain-derived neurotrophic factor (BDNF) receptor, TrkB, thereby increasing the survival and proliferation of cancer stem-like cells. Acetyl-CoA is a crucial co-substrate for initiation of the melatonergic pathway, as well as co-ordinating the interactions of OXPHOS and glycolysis in all cells of the tumour microenvironment. This provides a model of the tumour microenvironment that emphasises the roles of acetyl-CoA and the melatonergic pathway in shaping the dynamic intercellular metabolic interactions of the various cells within the tumour microenvironment. The potentiation of YY1 and GSK3β by O-GlcNAcylation will drive changes in metabolism in tumours and tumour microenvironment cells in association with their regulation of the melatonergic pathway. The emphasis on metabolic interactions across cell types in the tumour microenvironment provides novel future research and treatment directions.

scholarly journals Aryl Hydrocarbon Receptor Role in Co-Ordinating SARS-CoV-2 Entry and Symptomatology: Linking Cytotoxicity Changes in COVID-19 and Cancers; Modulation by Racial Discrimination Stress

Biology ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 249 ◽  
Author(s):  
George Anderson ◽  
Annalucia Carbone ◽  
Gianluigi Mazzoccoli
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Racial Discrimination ◽  
Inflammatory Cytokine ◽  
Future Research ◽  
Research Directions ◽  
Aryl Hydrocarbon ◽  
Future Research Directions ◽  
Pg E2 ◽  
Minority Ethnic

There is an under-recognized role of the aryl hydrocarbon receptor (AhR) in co-ordinating the entry and pathophysiology of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) that underpins the COVID-19 pandemic. The rise in pro-inflammatory cytokines during the ‘cytokine storm’ induce indoleamine 2,3-dioxygenase (IDO), leading to an increase in kynurenine that activates the AhR, thereby heightening the initial pro-inflammatory cytokine phase and suppressing the endogenous anti-viral response. Such AhR-driven changes underpin the heightened severity and fatality associated with pre-existent high-risk medical conditions, such as type II diabetes, as well as to how racial discrimination stress contributes to the raised severity/fatality in people from the Black Asian and Minority Ethnic (BAME) communities. The AhR is pivotal in modulating mitochondrial metabolism and co-ordinating specialized, pro-resolving mediators (SPMs), the melatonergic pathways, acetyl-coenzyme A, and the cyclooxygenase (COX) 2-prostaglandin (PG) E2 pathway that underpin ‘exhaustion’ in the endogenous anti-viral cells, paralleling similar metabolic suppression in cytolytic immune cells that is evident across all cancers. The pro-inflammatory cytokine induced gut permeability/dysbiosis and suppression of pineal melatonin are aspects of the wider pathophysiological underpinnings regulated by the AhR. This has a number of prophylactic and treatment implications for SARS-CoV-2 infection and cancers and future research directions that better investigate the biological underpinnings of social processes and how these may drive health disparities.

Aryl hydrocarbon receptor protects against viridans streptococci infection by activation of immune system through IL-17RA signaling

2015 ◽  
Vol 3 (2) ◽  
pp. 400-410
Author(s):  
Guowei Liang ◽  
Keyword(s):  
Immune Responses ◽  
Aryl Hydrocarbon Receptor ◽  
Bacterial Infections ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Microbial Infection ◽  
Viridans Streptococci ◽  
Coagulase Negative Staphylococci ◽  
Aryl Hydrocarbon

The majority of bacterial infections during neutropenia following high-dose chemotherapy or stem cell transplantation are caused by coagulase-negative staphylococci, a large number are due to viridans streptococci. Despite considerable progress in the understanding of the AhR-mediated regulation of immune responses, the role of AhR in bacterial infections has not been clearly demonstrated. In the study presented here, we sought to determine whether the aryl hydrocarbon receptor (AhR) would protect mice from infection with viridans streptococci. AhR enhances the inflammatory response to viridans streptococci stimuli. Specifically, neutrophil numbers and levels of inflammatory cytokines are often increased in mice treated with viridans streptococci. Furthermore, AhR activation through the IL-17RA is required for protection against viridans streptococcal infection. Taken together, we concluded that AhR plays an important role in optimal innate immunoprotection against microbial infection through the down-regulation of immune response.

scholarly journals Tryptophan Metabolites at the Crossroad of Immune-Cell Interaction via the Aryl Hydrocarbon Receptor: Implications for Tumor Immunotherapy

2021 ◽  
Vol 22 (9) ◽  
pp. 4644
Author(s):  
Marco Gargaro ◽  
Giorgia Manni ◽  
Giulia Scalisi ◽  
Paolo Puccetti ◽  
Francesca Fallarino
Keyword(s):  
Immune Responses ◽  
Aryl Hydrocarbon Receptor ◽  
Metabolic Pathways ◽  
Immune Cell ◽  
Tumor Immunotherapy ◽  
Cell Interaction ◽  
Qualitative And Quantitative ◽  
Adaptive Immune ◽  
Aryl Hydrocarbon ◽  
Tryptophan Metabolites

The Aryl hydrocarbon receptor (AhR) is a critical regulator of both innate and adaptive immune responses, with potent immunomodulatory effects that makes this receptor an attractive molecular target for novel therapeutics. Accumulating evidence indicates that diverse—both host’s and microbial—tryptophan metabolites profoundly regulate the immune system in the host via AhR, promoting either tolerance or immunity, largely as a function of the qualitative and quantitative nature of the metabolites being contributed by either source. Additional findings indicate that host and microbiota-derived tryptophan metabolic pathways can influence the outcome of immune responses to tumors. Here, we review recent studies on the role and modalities of AhR activation by various ligands, derived from either host-cell or microbial-cell tryptophan metabolic pathways, in the regulation of immune responses. Moreover, we highlight potential implications of those ligands and pathways in tumor immunotherapy, with particular relevance to checkpoint-blockade immune intervention strategies.

scholarly journals Bisphenols as a Legacy Pollutant, and Their Effects on Organ Vulnerability

2019 ◽  
Vol 17 (1) ◽  
pp. 112 ◽  
Author(s):  
Jong-Joo Kim ◽  
Surendra Kumar ◽  
Vinay Kumar ◽  
Yun-Mi Lee ◽  
You-Sam Kim ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
Case Control Studies ◽  
Aryl Hydrocarbon ◽  
Obesity And Diabetes ◽  
Low Concentrations ◽  
Increased Risk ◽  
Thermal Paper ◽  
Ros Formation ◽  
Dose Dependent ◽  
Global Influence

Bisphenols are widely used in the synthesis of polycarbonate plastics, epoxy resins, and thermal paper, which are used in manufacturing items of daily use. Packaged foods and drinks are the main sources of exposure to bisphenols. These chemicals affect humans and animals by disrupting the estrogen, androgen, progesterone, thyroid, and aryl hydrocarbon receptor functions. Bisphenols exert numerous harmful effects because of their interaction with receptors, reactive oxygen species (ROS) formation, lipid peroxidation, mitochondrial dysfunction, and cell signal alterations. Both cohort and case-control studies have determined an association between bisphenol exposure and increased risk of cardiovascular diseases, neurological disorders, reproductive abnormalities, obesity, and diabetes. Prenatal exposure to bisphenols results in developmental disorders in animals. These chemicals also affect the immune cells and play a significant role in initiating the inflammatory response. Exposure to bisphenols exhibit age, gender, and dose-dependent effects. Even at low concentrations, bisphenols exert toxicity, and hence deserve a critical assessment of their uses. Since bisphenols have a global influence on human health, the need to discover the underlying pathways involved in all disease conditions is essential. Furthermore, it is important to promote the use of alternatives for bisphenols, thereby restricting their uses.

scholarly journals Indoxyl sulfate impairs angiogenesis via chronic aryl hydrocarbon receptor activation

2021 ◽  
Author(s):  
Zachary R. Salyers ◽  
Madeline Coleman ◽  
Nicholas P. Balestrieri ◽  
Terence E. Ryan
Keyword(s):  
Cardiovascular Disease ◽  
Endothelial Cell ◽  
Aryl Hydrocarbon Receptor ◽  
Aortic Ring ◽  
Receptor Activation ◽  
Tube Formation ◽  
Indoxyl Sulfate ◽  
Aryl Hydrocarbon ◽  
Increased Risk ◽  
The Impact

Chronic kidney disease (CKD) is associated with a substantial increased risk of cardiovascular disease. There is growing evidence that uremic metabolites, which accumulate in the blood with CKD, have detrimental impacts on endothelial cell health and function. However, the molecular mechanisms by which uremic metabolites negatively impact endothelial cell biology are not fully understood. In this study, activation of the aryl hydrocarbon receptor (AHR) via indoxyl sulfate, a known uremic metabolite, was found to impair endothelial cell tube formation and proliferation, but not migratory function. Moreover, aortic ring cultures treated with indoxyl sulfate also exhibited decreased sprouting and high AHR activation. Next, genetic knockdown of the AHR using shRNA was found to rescue endothelial cell tube formation, proliferation, and aortic ring sprouting. Similarly, pharmacological AHR antagonism using resveratrol and CH223191 were also found to rescue angiogenesis in cell and aortic ring cultures. Finally, a constitutively active AHR (CAAHR) vector was generated and used to confirm AHR-specific effects. Expression of the CAAHR recapitulated the impaired tube formation and proliferation in cultured endothelial cells and decreased sprouting in aortic ring cultures. Taken together, these data define the impact of AHR activation on angiogenesis and highlight the potential for therapeutic AHR antagonists which may improve angiogenesis in the context of CKD and cardiovascular disease.

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