Image credit: http://www.nature.com/nrc/journal/v14/n12/full/nrc3846.html
The aryl hydrocarbon receptor (AhR) is responsible for helping cell growth and response to outside factors that test the body’s immune system response. AhRs are necessary for cell differentiation and growth in various organ systems to keep homeostasis. AhRs are important and necessary in promoting a healthy lifestyle away from disease and infection due to outside forces. Keep reading to learn more about AhRs.
What is Aryl Hydrocarbon Receptor?
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 participate in when the body is at homeostasis (R).
The Roles of the Aryl Hydrocarbon Receptor
1) The AhR Maintains Homeostasis
AhR receptors are responsible for transmitting environmental cues to the lymphocytes, which then trigger the required immune system to regulate the body, maintaining homeostasis (R).
With regards to cell cycle regulation, the AhR is responsible for the activation of mitogen-activated protein kinases, which controls other proteins (R).
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 (R).
AhR is critical for controlling differentiation, growth, and function of mast cells (R).
In mice, AhR is responsible for limiting intestinal epithelial cell inflammation and even returning mice with sulfate-induced colitis back to homeostasis (R).
AhR in mice helps reduce the symptoms of colitis, returning the body to homeostasis (R).
In fetal mice, AhR development through embryonic stem cells is responsible for coordinating and differentiating heart cells (R).
AhR during development is the coordinator for the complex regulatory network responsible for maintaining cardiovascular homeostasis (R).
In both lean and obese mice, AhR receptors are responsible for helping maintain glucose homeostasis in the body (R).
In mice who have a fatty liver, activated human AhR receptors successfully negated the effects of a fatty liver while maintaining proper energy homeostasis (R).
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 (R).
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 (R).
2) Aryl Hydrocarbon Receptors Assists the Immune System
AhRs are responsible for recognizing polycyclic aromatic hydrocarbons, an environmental contaminant that can cause cancer. AhRs then signals the body to prevent physiological harm (R).
In human cell lines exposed to varying levels of lead, AhRs controlling xenobiotic (substances foreign to the body) metabolism was affected and in turn induced mRNA expression to prevent any further complication with xenobiotic metabolism (R).
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 (R).
As for patients suffering from tuberculosis, greater expression of AhRs increased overall innate immune response through the formation of lymphoid cells (R).
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 (R).
In mice, AhRs maintain critical gut microbiota. The AhRs also modify the gut microbiota homeostasis due to organic contaminants. If there is an infection, AhRs will increase the immune response in order to kill off the secondary organic infection (R).
Natural Ways to Activate the AhR
Ligands can either activate or inhibit AhRs. This depends on the type of ligand that binds to the receptor. The major ligand responsible for AhR activation is 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. This Kynurenine pathway is responsible for forming a positive feedback loop, allowing constant activation of AhRs (R).
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 (R).
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 downregulates CYP1 enzymes that would inhibit AhRs and it allows for further binding of other ligands on AhRs (R).
4) Tryptophan Photometabolites
Tryptophan photometabolites are endogenous AhR ligands that signal activation at nanomolar concentrations. These photometabolites block inflammatory responses and increase AhR functionality in the skin to prevent damage and to promote healthy, protected skin cells (R).
However, the most natural activators of AhRs are phytochemicals that act as ligands to activate T-cell development, autoimmunity, and inflammation reduction. Unfortunately, these phytochemicals are some of the most ineffective at activating AhRs (R).
Inhibiting the Aryl Hydrocarbon Receptor
Inhibiting AhRs come 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. This can end up reducing immune system functionality overall (R).
- AhR is responsible for controlling the potent ligand tetrachloro dibenzo-p-dioxin (R).
- It is also responsible for the interaction with retinoblastoma proteins during the cell cycle (R).
- AhR in mice inhibits miR-212/132m which in turn reduces the symptoms of colitis, returning the body to homeostasis (R).
- In both lean and obese mice, AhR receptors are responsible for limiting the binding capabilities of coplanar polychlorinated biphenyls. This also helps maintain glucose homeostasis in the body (R).
- The interaction with transforming growth factor-beta1 and the AhR receptor in prostate endothelial cells is responsible for the development of the prostate and expression of xenobiotic metabolizing enzymes (R).