Aryl Hydrocarbon Receptor (AhR) Roles and Functions

Aryl Hydrocarbon Receptor (AhR) Roles and Functions

Aryl Hydrocarbon Receptor (AhR) Roles and Functions

The aryl hydrocarbon receptor (AhR) is responsible for supporting cell growth and immune system response to outside threats, especially environmental pollutants. AhRs are necessary for cell differentiation and growth in various organ systems. Keep reading to learn the roles of AhR and factors that activate/block it.

What is Aryl Hydrocarbon Receptor?

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor responsible for controlling the expression of various sets of genes [1].

Both AhR and its partner, aryl hydrocarbon nuclear translocator, are associated with how an organism responds to environmental contaminants, mostly man-made ones. However, current research has determined different physiological roles that AhRs plays in the absence of contaminants [1].

The Roles of the Aryl Hydrocarbon Receptor

The role of AhR in the human body is complex and not yet fully understood. Most of the findings below stem from animal and cell-based studies. They give us a good idea about the potential roles and functions of AhR, but the results may not always translate to humans.

Cardiovascular

In fetal mice, AhR development through embryonic stem cells is responsible for coordinating and differentiating heart cells [2].

AhR during development is the coordinator for the complex regulatory network responsible for maintaining cardiovascular homeostasis [2].

In both lean and obese mice, AhR receptors are responsible for helping maintain glucose homeostasis in the body [3].

In mice who have a fatty liver, activated human AhR receptors successfully negated the effects of a fatty liver while maintaining proper energy balance [4].

AhRs interact with stem cells to signal for cellular regeneration, in the context of aging and diseases. The receptors specifically target the metabolic efficacy of cell regeneration vs. cell cycling [5].

Toxin Removal

AhRs are responsible for recognizing polycyclic aromatic hydrocarbons, environmental contaminants that can contribute to cancer development. AhRs then signals the body to prevent physiological harm [6].

In human cell lines exposed to varying levels of lead, AhRs help prevent the harm [7].

Lymphocytes

AhR receptors are responsible for transmitting environmental cues to the lymphocytes, which then trigger the required immune system to regulate the body, maintaining homeostasis [8].

In dairy cows bred in a dioxin-contaminated area, AhR gene expression significantly increased to increase the number of circulating lymphocytes to fight the toxin contamination [9].

As for patients suffering from tuberculosis, a greater expression of AhRs increased overall innate immune response through the formation of lymphoid cells [10].

T Cells

In mice, AhR is responsible for the maintenance of epidermal T cells, which regulate cell maturation in the skin. This helps maintain the immune system for the skin [11].

Humans who are exposed to environmental contaminants leading to a viral infection had increased T-cell response and regulation after activating AhRs. T-cell responses in the lymph nodes were also increased, to eliminate the viral infection throughout the patient’s body [12].

Mast Cells

AhR is critical for controlling differentiation, growth, and function of mast cells [13].

Mast cells exposed to AhR ligands had increased calcium and reactive oxygen species leading to increased mast cell signaling, degranulation, and cytokine releases [13].

Gut Health

Tryptophan plays an important role in maintaining gut immune system homeostasis. AhR in mice increases the intake of tryptophan which balances the mucosal response in the gut, allowing for the survival of mixed microbial communities [14].

Therefore, AhRs maintain gut microbiota balance and modify it in the presence of organic contaminants or pathogens. If there is an infection, AhRs will increase the immune response in order to suppress it [15].

In mice, AhR is responsible for limiting intestinal epithelial cell inflammation and even healing mice with drug-induced colitis [16].

Pathways That Activate the AhR

Ligands can either activate or inhibit AhRs. This depends on the type of ligand that binds to the receptor. The major ligands responsible for AhR activation are tryptophan-derived metabolites. There are at least five pathways that lead to the activation of AhR.

1) Kynurenine Pathway

The primary activation in mammals is through the kynurenine pathway. Glioblastomas (brain tumors) produce kynurenine and is responsible for their survival through activating AhRs. It also increases regulatory T-Cells responsible for increasing autoimmune function [17].

This Kynurenine pathway is responsible for forming a positive feedback loop, allowing constant activation of AhRs.

2) Dopamine Decarboxylase Pathway

The dopamine decarboxylase pathway is also responsible for AhR activation through direct binding with the receptor. Not only is it a direct binder to AhR, but it also serves as a downstream precursor for AhR ligands [17].

3) Serotonin Pathway

The serotonin pathway that comes from tryptophan is also responsible for AhR activation. This is due to its weak affinity for the receptor. It decreases CYP1 enzymes that would inhibit AhRs and it allows for further binding of other ligands on AhRs [17].

Tryptophan photometabolites are endogenous AhR ligands that signal activation at nanomolar concentrations. They block inflammatory responses and increase AhR functionality in the skin to prevent damage and to promote healthy, protected skin cells [17].

5) Phytochemicals

Natural activators of AhRs include phytochemicals that act as ligands to activate T-cell development, autoimmunity, and inflammation reduction. Unfortunately, these phytochemicals are some of the least effective AhR activators [17].

AhR Inhibition

AhR inhibition comes from environmental chemicals that are responsible for limiting cell differentiation and reducing immune system responses.

Inhibition of the AhRs can be detrimental to the health of various organ systems. This includes the cardiovascular system, the skin, and the digestive tract. Without proper AhR activation, this limits the development of mature B cells and their responses, which may weaken the immune response [18].

Source: https://selfhacked.com/blog/aryl-hydrocarbon-receptor-ahr/

Online Mendelian Inheritance in Man (OMIM)

Aryl Hydrocarbon Receptor (AhR) Roles and Functions

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Source: https://www.omim.org/entry/600253

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Another Important Biological Function for the Aryl Hydrocarbon Receptor

Aryl Hydrocarbon Receptor (AhR) Roles and Functions

For many years, the aryl hydrocarbon receptor (AhR) had been studied primarily for its contribution to environmental chemical-induced organ toxicity or carcinogenicity.

1–3 The prevailing paradigm fashioned from these studies held that activation of the cytosolic AhR by any one of a variety of environmental pollutants (eg, planar polychlorinated biphenyls, polycyclic aromatic hydrocarbons, and dioxins) results in nuclear AhR translocation and transcriptional upregulation of prototypic target genes encoding cytochrome P450 enzymes (eg, CYP1A1 and CYP1B1).4–6 These enzymes are capable of metabolizing at least some of the environmental AhR ligands into toxic or mutagenic intermediates, thereby affecting biological outcomes. Although these studies were extremely important for defining the AhR as an environmental ligand-induced transcription factor and in mapping out portions of the AhR signaling pathway, they did not directly provide evidence of the “normal” physiological function of this evolutionarily conserved7 protein. However, in the last few years, it has become evident that the AhR is involved in several critical cellular functions, including but not limited to regulation of normal and neoplastic cell growth,8–12 invasion,13–18 and apoptosis.19–23 Most recently, an important role for the AhR in the development or function of T-cell subsets that mediate or regulate autoimmunity and tumor immunity, ie, helper T cells (Th17) and regulatory T cells, has been demonstrated.24–28 Now, Wu et al demonstrate yet another important immune system–related function of the AhR, regulation of macrophage-dependent inflammation contributing to atherosclerosis.

See accompanying article on page 1260

Previous studies performed by Vogel et al provided important information on the effects of AhR activation in monocytes/macrophages.

29,30 Specifically, they demonstrated that, in a macrophage cell line, activated AhR physically interacts with the RelB subunit of nuclear factor-κB, a well-known contributor to inflammatory processes, and induces production of inflammatory cytokines and extracellular matrix-degrading matrix metalloproteinases.

Their demonstration that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (dioxin) induces phenotypic changes characteristic of foam cells provided evidence that the AhR, activated either by some endogenous ligand or by environmental ligands such as TCDD or polycyclic aromatic hydrocarbons in cigarette smoke, plays a role in the formation of atherosclerotic plaques. Here, Wu et al31 extend these studies to demonstrate, very clearly, that AhR activation does indeed contribute to the formation of atherosclerotic plaques in apolipoprotein E−/− mice whether or not mice are fed an atherogenic high-fat diet. Moreover, they demonstrate that the ly signaling pathway leading from AhR activation to atherosclerotic plaque formation involves induction of matrix metalloproteinase-12, the proinflammatory cytokines/chemokines interleukin-8 (IL-8) and keratin chemoattractant, activation of CXC chemokine receptor (a receptor for several inflammatory molecules, including IL-8 and keratin chemoattractant), and ultimately production of the CXCR2 target gene VEGF (Figure). These studies were performed in the context of exposure to TCDD or the complex chemical mixture found in cigarette smoke extract. As such, they provide, for the first time, a molecular and cellular pathway that may account for the association between exposure to TCDD or cigarette smoke and increased risk of atherosclerosis. Just as importantly, these studies, together with those demonstrating AhR-regulated, Th17-mediated inflammatory responses, strongly support the hypothesis that the AhR plays a central role in both T-cell and macrophage-mediated inflammation in several tissues. Furthermore, they suggest the intriguing possibility that the AhR may serve as a therapeutic target for downregulation of vascular inflammatory responses. As such, this work from the Vogel laboratory helps transport the AhR from the circumscribed realm of a “sensor of toxin exposure” to the more generalized and perhaps more clinically relevant world of “mediator of pathological inflammation.”

Figure. A model of AhR control of vascular inflammation.

AhR activation in vascular macrophages by environmental ligands (TCDD, polycyclic aromatic hydrocarbon in cigarette smoke) leads to upregulation of matrix metalloproteinase-12 (MMP-12), monocyte chemoattractant protein-1 (MCP-1), IL-8, and keratin chemoattractant (KC).

Matrix metalloproteinase-12 contributes to extracellular matrix (ECM) degradation; MCP-1 and IL-8 recruit and activate inflammatory cells to vascular endothelium; and IL-8 and KC activate the CXCR2 chemokine receptor on macrophages or infiltrating neutrophils, resulting in transcriptional upregulation of vascular endothelial growth factor (VEGF) and increased vascular endothelial cell growth. Collectively, the coordinated upregulation of these mediators of inflammation contributes to formation of the atherosclerotic plaque.

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Source: https://www.ahajournals.org/doi/full/10.1161/atvbaha.111.227553

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