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Relationship between Inflammation and Aryl Hydrocarbon Receptor Pathway
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Relationship between Inflammation and Aryl Hydrocarbon Receptor Pathway

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (15 November 2021) | Viewed by 31938

Special Issue Editor

Prof. Dr. Tiziana Guarnieri

E-Mail Website
Guest Editor
Department of Biology, Geology and Environmental Sciences (BiGeA), Alma Mater Studiorum—Università di Bologna, 40126 Bologna, Italy
Interests: inflammation; aryl hydrocarbon receptor; cell physiology; cell signaling; endocrine interference; nonsteroidal anti-inflammatory drugs (NSAIDs)
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The aryl hydrocarbon receptor (AhR) has long been known as an endogenous biosensor linking different environmental stresses to cellular homeostatic mechanisms and detoxification processes. Its evolutionary conservation and the gene sets that are responsive to this transcription factor highlight its participation in basic physiological processes such as cell growth and differentiation, and in the inflammatory response. In fact, AhR plays a central modulatory role in the immune system and is also emerging as a key player in inflammatory processes that are triggered by several physiologic and pathologic settings in different tissues. In the last two decades, research with AhR-knockout mice has highlighted AhR participation in the homeostasis of almost all physiologic systems, with both genomic and nongenomic mechanisms, which frequently interact with inflammation pathways. In addition, the variety of endogenous and exogenous ligands that interfere with AhR signalling points out its role beyond detoxification processes and is helping to elucidate its contribution in cell transitions to inflammatory states and in their resolution.

This call meets the growing need to draw a coherent framework describing the participation of the AhR pathway in the management of inflammatory processes in different cell types. We will appreciate papers reporting the contribution of AhR, both in the onset and in the resolution of inflammation in physiological and pathological settings, including the recently reported SARS-CoV-2-induced inflammation. Evolutionary perspectives about AhR functions are also welcome.

Prof. Tiziana Guarnieri
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • aryl hydrocarbon receptor
  • biosensor
  • xenobiotics
  • ligands
  • inflammation
  • immune system
  • homeostasis
  • cellular signalling
  • evolution

Related Special Issue

Published Papers (8 papers)

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Research

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32 pages, 45552 KiB  
Article
Aryl Hydrocarbon Receptor Activation by Benzo[a]pyrene Prevents Development of Septic Shock and Fatal Outcome in a Mouse Model of Systemic Salmonella enterica Infection
by Christiane Fueldner, Sina Riemschneider, Janine Haupt, Harald Jungnickel, Felix Schulze, Katharina Zoldan, Charlotte Esser, Sunna Hauschildt, Jens Knauer, Andreas Luch, Stefan Kalkhof and Jörg Lehmann
Cells 2022, 11(4), 737; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11040737 - 20 Feb 2022
Cited by 5 | Viewed by 2832
Abstract
This study focused on immunomodulatory effects of aryl hydrocarbon receptor (AhR) activation through benzo[a]pyrene (BaP) during systemic bacterial infection. Using a well-established mouse model of systemic Salmonella enterica (S.E.) infection, we studied the influence of BaP on the cellular and humoral [...] Read more.
This study focused on immunomodulatory effects of aryl hydrocarbon receptor (AhR) activation through benzo[a]pyrene (BaP) during systemic bacterial infection. Using a well-established mouse model of systemic Salmonella enterica (S.E.) infection, we studied the influence of BaP on the cellular and humoral immune response and the outcome of disease. BaP exposure significantly reduced mortality, which is mainly caused by septic shock. Surprisingly, the bacterial burden in BaP-exposed surviving mice was significantly higher compared to non-exposed mice. During the early phase of infection (days 1–3 post-infection (p.i.)), the transcription of proinflammatory factors (i.e., IL-12, IFN-γ, TNF-α, IL-1β, IL-6, IL-18) was induced faster under BaP exposure. Moreover, BaP supported the activity of antigen-presenting cells (i.e., CD64 (FcγRI), MHC II, NO radicals, phagocytosis) at the site of infection. However, early in infection, the anti-inflammatory cytokines IL-10 and IL-22 were also locally and systemically upregulated in BaP-exposed S.E.-infected mice. BaP-exposure resulted in long-term persistence of salmonellae up to day 90 p.i., which was accompanied by significantly elevated S.E.-specific antibody responses (i.e., IgG1, IgG2c). In summary, these data suggest that BaP-induced AhR activation is capable of preventing a fatal outcome of systemic S.E. infection, but may result in long-term bacterial persistence, which, in turn, may support the development of chronic inflammation. Full article
(This article belongs to the Special Issue Relationship between Inflammation and Aryl Hydrocarbon Receptor Pathway)
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19 pages, 2862 KiB  
Article
Aryl Hydrocarbon Receptor (AhR) Limits the Inflammatory Responses in Human Lung Adenocarcinoma A549 Cells via Interference with NF-κB Signaling
by Gerardo Vázquez-Gómez, Martina Karasová, Zuzana Tylichová, Markéta Kabátková, Aleš Hampl, Jason Matthews, Jiří Neča, Miroslav Ciganek, Miroslav Machala and Jan Vondráček
Cells 2022, 11(4), 707; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11040707 - 17 Feb 2022
Cited by 7 | Viewed by 2416
Abstract
Apart from its role in the metabolism of carcinogens, the aryl hydrocarbon receptor (AhR) has been suggested to be involved in the control of inflammatory responses within the respiratory tract. However, the mechanisms responsible for this are only partially known. In this study, [...] Read more.
Apart from its role in the metabolism of carcinogens, the aryl hydrocarbon receptor (AhR) has been suggested to be involved in the control of inflammatory responses within the respiratory tract. However, the mechanisms responsible for this are only partially known. In this study, we used A549 cell line, as a human model of lung alveolar type II (ATII)-like cells, to study the functional role of the AhR in control of inflammatory responses. Using IL-1β as an inflammation inducer, we found that the induction of cyclooxygenase-2 and secretion of prostaglandins, as well as expression and release of pro-inflammatory cytokines, were significantly higher in the AhR-deficient A549 cells. This was linked with an increased nuclear factor-κB (NF-κB) activity, and significantly enhanced phosphorylation of its regulators, IKKα/β, and their target IκBα, in the AhR-deficient A549 cells. In line with this, when we mimicked the exposure to a complex mixture of airborne pollutants, using an organic extract of reference diesel exhaust particle mixture, an exacerbated inflammatory response was observed in the AhR-deficient cells, as compared with wild-type A549 cells. Together, the present results indicate that the AhR may act as a negative regulator of the inflammatory response in the A549 model, via a direct modulation of NF-κB signaling. Its role(s) in the control of inflammation within the lung alveoli exposed to airborne pollutants, especially those which simultaneously activate the AhR, thus deserve further attention. Full article
(This article belongs to the Special Issue Relationship between Inflammation and Aryl Hydrocarbon Receptor Pathway)
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14 pages, 2995 KiB  
Article
Inhibition of Human Osteoclast Differentiation by Kynurenine through the Aryl-Hydrocarbon Receptor Pathway
by So-Yeon Kim, Younseo Oh, Sungsin Jo, Jong-Dae Ji and Tae-Hwan Kim
Cells 2021, 10(12), 3498; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10123498 - 10 Dec 2021
Cited by 4 | Viewed by 3302
Abstract
Aryl-hydrocarbon receptor (AhR) is a ligand-activated transcription factor and regulates differentiation and function of various immune cells such as dendritic cells, Th17, and regulatory T cells. In recent studies, it was reported that AhR is involved in bone remodeling through regulating both osteoblasts [...] Read more.
Aryl-hydrocarbon receptor (AhR) is a ligand-activated transcription factor and regulates differentiation and function of various immune cells such as dendritic cells, Th17, and regulatory T cells. In recent studies, it was reported that AhR is involved in bone remodeling through regulating both osteoblasts and osteoclasts. However, the roles and mechanisms of AhR activation in human osteoclasts remain unknown. Here we show that AhR is involved in human osteoclast differentiation. We found that AhR expressed highly in the early stage of osteoclastogenesis and decreased in mature osteoclasts. Kynurenine (Kyn), formylindolo[3,4-b] carbazole (FICZ), and benzopyrene (BaP), which are AhR agonists, inhibited osteoclast formation and Kyn suppressed osteoclast differentiation at an early stage. Furthermore, blockade of AhR signaling through CH223191, an AhR antagonist, and knockdown of AhR expression reversed Kyn-induced inhibition of osteoclast differentiation. Overall, our study is the first report that AhR negatively regulates human osteoclast differentiation and suggests that AhR could be good therapeutic molecule to prevent bone destruction in chronic inflammatory diseases such as rheumatoid arthritis (RA). Full article
(This article belongs to the Special Issue Relationship between Inflammation and Aryl Hydrocarbon Receptor Pathway)
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Review

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27 pages, 2302 KiB  
Review
Current Therapeutic Landscape and Safety Roadmap for Targeting the Aryl Hydrocarbon Receptor in Inflammatory Gastrointestinal Indications
by Samantha C. Faber, Tejas S. Lahoti, Ewan R. Taylor, Lauren Lewis, Jessica M. Sapiro, Vicencia Toledo Sales, Yvonne P. Dragan and Brandon D. Jeffy
Cells 2022, 11(10), 1708; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11101708 - 21 May 2022
Cited by 3 | Viewed by 3361
Abstract
Target modulation of the AhR for inflammatory gastrointestinal (GI) conditions holds great promise but also the potential for safety liabilities both within and beyond the GI tract. The ubiquitous expression of the AhR across mammalian tissues coupled with its role in diverse signaling [...] Read more.
Target modulation of the AhR for inflammatory gastrointestinal (GI) conditions holds great promise but also the potential for safety liabilities both within and beyond the GI tract. The ubiquitous expression of the AhR across mammalian tissues coupled with its role in diverse signaling pathways makes development of a “clean” AhR therapeutically challenging. Ligand promiscuity and diversity in context-specific AhR activation further complicates targeting the AhR for drug development due to limitations surrounding clinical translatability. Despite these concerns, several approaches to target the AhR have been explored such as small molecules, microbials, PROTACs, and oligonucleotide-based approaches. These various chemical modalities are not without safety liabilities and require unique de-risking strategies to parse out toxicities. Collectively, these programs can benefit from in silico and in vitro methodologies that investigate specific AhR pathway activation and have the potential to implement thresholding parameters to categorize AhR ligands as “high” or “low” risk for sustained AhR activation. Exploration into transcriptomic signatures for AhR safety assessment, incorporation of physiologically-relevant in vitro model systems, and investigation into chronic activation of the AhR by structurally diverse ligands will help address gaps in our understanding regarding AhR-dependent toxicities. Here, we review the role of the AhR within the GI tract, novel therapeutic modality approaches to target the AhR, key AhR-dependent safety liabilities, and relevant strategies that can be implemented to address drug safety concerns. Together, this review discusses the emerging therapeutic landscape of modalities targeting the AhR for inflammatory GI indications and offers a safety roadmap for AhR drug development. Full article
(This article belongs to the Special Issue Relationship between Inflammation and Aryl Hydrocarbon Receptor Pathway)
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19 pages, 1082 KiB  
Review
Hypothesis: Emerging Roles for Aryl Hydrocarbon Receptor in Orchestrating CoV-2-Related Inflammation
by Tiziana Guarnieri
Cells 2022, 11(4), 648; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11040648 - 13 Feb 2022
Cited by 13 | Viewed by 3605
Abstract
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the pathogenic agent of Coronavirus-Induced Disease-2019 (COVID-19), a multi-organ syndrome which primarily targets the respiratory system. In this review, considering the large amount of data pointing out the role of the Aryl hydrocarbon Receptor (AhR) in [...] Read more.
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the pathogenic agent of Coronavirus-Induced Disease-2019 (COVID-19), a multi-organ syndrome which primarily targets the respiratory system. In this review, considering the large amount of data pointing out the role of the Aryl hydrocarbon Receptor (AhR) in the inflammatory response and in the modulation of innate and adaptive immunity, we describe some mechanisms that strongly suggest its involvement in the management of COVID-19′s inflammatory framework. It regulates both the expression of Angiotensin Converting Enzyme-2 (ACE-2) and its stabilizing partner, the Broad neutral Amino acid Transporter 1 (B0AT1). It induces Indolamine 2,3 dioxygenase (IDO-1), the enzyme which, starting from Tryptophan (Trp), produces Kynurenine (Kyn, Beta-Anthraniloyl-L-Alanine). The accumulation of Kyn and the depletion of Trp arrest T cell growth and induce apoptosis, setting up an immune-tolerant condition, whereas AhR and interferon type I (IFN-I) build a mutual inhibitory loop that also involves NF-kB and limits the innate response. AhR/Kyn binding boosts the production of Interleukin-6 (IL-6), thus reinforcing the inflammatory state and counteracting the IDO-dependent immune tolerance in the later stage of COVID-19. Taken together, these data depict a framework where sufficient clues suggest the possible participation of AhR in the management of COVID-19 inflammation, thus indicating an additional therapeutic target for this disease. Full article
(This article belongs to the Special Issue Relationship between Inflammation and Aryl Hydrocarbon Receptor Pathway)
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13 pages, 652 KiB  
Review
Role of Aryl Hydrocarbon Receptor Activation in Inflammatory Chronic Skin Diseases
by Maddalena Napolitano, Gabriella Fabbrocini, Fabrizio Martora, Vincenzo Picone, Paola Morelli and Cataldo Patruno
Cells 2021, 10(12), 3559; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10123559 - 16 Dec 2021
Cited by 39 | Viewed by 4654
Abstract
Aryl Hydrocarbon Receptor (AhR) is an evolutionary transcription factor which acts as a crucial sensor of different exogenous and endogenous molecules Recent data indicate that AhR is implicated in several physiological processes such as cell physiology, host defense, proliferation and differentiation of immune [...] Read more.
Aryl Hydrocarbon Receptor (AhR) is an evolutionary transcription factor which acts as a crucial sensor of different exogenous and endogenous molecules Recent data indicate that AhR is implicated in several physiological processes such as cell physiology, host defense, proliferation and differentiation of immune cells, and detoxification. Moreover, AhR involvement has been reported in the development and maintenance of several pathological conditions. In recent years, an increasing number of studies have accumulated highlighting the regulatory role of AhR in the physiology of the skin. However, there is evidence of both beneficial and harmful effects of AHR signaling. At present, most of the evidence concerns inflammatory skin diseases, in particular atopic dermatitis, psoriasis, acne, and hidradenitis suppurativa. This review exam-ines the role of AhR in skin homeostasis and the therapeutic implication of its pharmacological modulation in these cutaneous inflammatory diseases. Full article
(This article belongs to the Special Issue Relationship between Inflammation and Aryl Hydrocarbon Receptor Pathway)
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27 pages, 2234 KiB  
Review
Role of AHR Ligands in Skin Homeostasis and Cutaneous Inflammation
by Nieves Fernández-Gallego, Francisco Sánchez-Madrid and Danay Cibrian
Cells 2021, 10(11), 3176; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10113176 - 15 Nov 2021
Cited by 43 | Viewed by 6322
Abstract
Aryl hydrocarbon receptor (AHR) is an important regulator of skin barrier function. It also controls immune-mediated skin responses. The AHR modulates various physiological functions by acting as a sensor that mediates environment–cell interactions, particularly during immune and inflammatory responses. Diverse experimental systems have [...] Read more.
Aryl hydrocarbon receptor (AHR) is an important regulator of skin barrier function. It also controls immune-mediated skin responses. The AHR modulates various physiological functions by acting as a sensor that mediates environment–cell interactions, particularly during immune and inflammatory responses. Diverse experimental systems have been used to assess the AHR’s role in skin inflammation, including in vitro assays of keratinocyte stimulation and murine models of psoriasis and atopic dermatitis. Similar approaches have addressed the role of AHR ligands, e.g., TCDD, FICZ, and microbiota-derived metabolites, in skin homeostasis and pathology. Tapinarof is a novel AHR-modulating agent that inhibits skin inflammation and enhances skin barrier function. The topical application of tapinarof is being evaluated in clinical trials to treat psoriasis and atopic dermatitis. In the present review, we summarize the effects of natural and synthetic AHR ligands in keratinocytes and inflammatory cells, and their relevance in normal skin homeostasis and cutaneous inflammatory diseases. Full article
(This article belongs to the Special Issue Relationship between Inflammation and Aryl Hydrocarbon Receptor Pathway)
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16 pages, 1599 KiB  
Review
The Role of AhR in the Hallmarks of Brain Aging: Friend and Foe
by Emmanuel S. Ojo and Shelley A. Tischkau
Cells 2021, 10(10), 2729; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10102729 - 13 Oct 2021
Cited by 23 | Viewed by 3945
Abstract
In recent years, aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, has been considered to be involved in aging phenotypes across several species. This receptor is a highly conserved biosensor that is activated by numerous exogenous and endogenous molecules, including microbiota metabolites, to [...] Read more.
In recent years, aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, has been considered to be involved in aging phenotypes across several species. This receptor is a highly conserved biosensor that is activated by numerous exogenous and endogenous molecules, including microbiota metabolites, to mediate several physiological and toxicological functions. Brain aging hallmarks, which include glial cell activation and inflammation, increased oxidative stress, mitochondrial dysfunction, and cellular senescence, increase the vulnerability of humans to various neurodegenerative diseases. Interestingly, many studies have implicated AhR signaling pathways in the aging process and longevity across several species. This review provides an overview of the impact of AhR pathways on various aging hallmarks in the brain and the implications for AhR signaling as a mechanism in regulating aging-related diseases of the brain. We also explore how the nature of AhR ligands determines the outcomes of several signaling pathways in brain aging processes. Full article
(This article belongs to the Special Issue Relationship between Inflammation and Aryl Hydrocarbon Receptor Pathway)
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