Aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease

As these GEITP pages have discussed previously, the ligand-activated transcription factor aryl hydrocarbon receptor (AHR), is one of 110 members of the human BHLH gene superfamily of sensors that continuously monitor incoming signals (both exogenous and endogenous i.e. from both outside, and within, the organism) that can affect each cell type, one way or another (these signals include oxygen tension, redox potential, temperature, osmotic pressure, and many types of endogenous and exogenous chemicals). Cells are constantly adapting and responding to these molecular signals in their micromilieu — provided by environment, diet, commensal flora (i.e. all beneficial virus-bactera-fungus that live synergistically within our bodies), and host metabolism. AHR is a member of a BHLH subset, called the basic helix-loop-helix periodic circadian protein (Per)–AHR nuclear translocator (ARNT)–single-minded protein (Sim) (bHLH/PAS), which comprises ~30 members.

Table 1

Summary of organs, systems,cell functions, and developmental biology in which AHR-signaling is involved. Location AHR-signaling pathway involvement

Central nervous system — Development of brain and nervous system; Neurogenesis; Neuronal cell development; Cardiorespiratory brainstem – development in ventrolateral medulla; “Brain-gut-microbiome”

Eye — Ciliary body formation and function; Thyroid-associated eye disease

Gastrointestinal tract — Development of GI tract; Rectal prolapse during aging; “Brain-gut-microbiome”

Heart — Development of heart organ; Cardiovascular physiology; Atherogenesis; Cardiomyogenesis; Cardiorespiratory — functions

Hematological system — Development of blood cell-forming system; Hematopoiesis; Activation or suppression of erythroid development

Immune system — Immune system development; The immune response; Innate immunity; Pro-inflammatory response; Anti-inflammatory response; Immunomodulatory effects

Inner ear — Development of the cochlea

Kidney — Development of the kidney; Hypertension

Liver — Development of liver organ; Hyperlipidemia; Glucose and lipid metabolism; Hepatic steatosis

Musculoskeletal system — Transmesoderm ? osteoblast transition; Bone formation; Osteoclastogenesis

Pancreas — Development of pancreas; Beta-cell regulation; Pancreatic fibrosis

Endocrine system — Serum lowered testosterone levels; Infertility; Mammary gland duct cell epithelial hyperplasia; Degenerative changes in testis; Gerrm-cell apoptosis; Endometriosis

Reproductive system — Development of male and female sex organs; Spermatogenesis; Fertility

Respiratory tract– Development of respiratory tract; Disruption of GABA-ergic transmission defects; Cardiorespiratory function

Vascular system — Angiogenesis; Atherosclerotic plaque formation

Skin– Barrier physiology; Atopic dermatitis

Cellular functions — Cell migration; Cell adhesion; Circadian rhythmicity

DNA changes — DNA synthesis; DNA repair; DNA-adduct formation; Mutagenesis

Oxidative stress — Mitochondrial ROS formation; Anti-oxidant protection against ROS formation; Mitochondrial H2O2 production; Crosstalk with hypoxia and HIF-signaling pathways; Transforming growth factor-signaling pathways; MID1-PP2A-CDC25B-CDK1 signaling pathway regulating mitosis

Tumor cells– Growth suppression; Tumor initiation; Tumor promotion

ES cell basic functions — Ectoderm ? epithelium transition; Cell adhesion; Cell-cycle regulation; Apoptosis; Cavitation during morula? blastula formation; Activator of Rho/Rac GTPases; WNT-signaling pathways; Homeobox-signaling pathways

Other basic functions — Transgenerational inheritance; Epigenetic effects; Chromatin remodeling; Histone modification; Aging-related and degenerative diseases

After discovery of the Per locus (in the fly) in 1971, AHR was the second bHLH/PAS member discovered 3 years later; AHR is now known to carry out functions in virtually every cell-type of the body — resulting in regulation of critical life processes, as well as protecting against disease and causing disease [reviewed in Progr Lipid Res 2017; 67: 38-57]. In the attached review, authors describe updated information about AHR participation in the immune response. Authors suggest that “studying AHR regulation and function is likely to reveal unknown biological processes and may guide the development of novel therapeutic interventions.” My opinion strongly disagrees with this suggestion: i.e. any gene/gene product expressed from the fertilized cell and embryonic stems cells — and then throughout development and all the way to carrying out critical life functions in virtually every cell-type — will be a difficult drug target (down- or up-regulating AHR, other than only specifically that one cell type, will lead to many so-called ‘off-targets’ that might cause detrimental clinical effects).

Authors [see attached review] summarize current knowledge on the role of AHR in autoimmune disorders and cancer of the central nervous system (CNS). AHR is described as a transcription factor that integrates environmental, dietary, microbial, and metabolic cues to control complex transcriptional programs in a ligand-specific, cell-type-specific, and context-specific manner. Authors update and recapitulate current knowledge of AHR and the transcriptional pathways it controls in the immune system. Lastly, authors discuss the purported role of AHR in autoimmune diseases and neoplasia (cancer) of the CNS, with special focus on the gut immune system, the brain-gut-microbiome axis, and the “therapeutic potential of targeting AHR” in neurological disorders.
Nat Rev Immunol 4 Feb 2o19; doi: 10.1038/s41577-019-0125-8. [Epub ahead of print]

Nancy, this is an excellent point you make, which needs to be scrutinized closely. No doubt my opinion (which has changed, over the decades) has been strongly influenced by advances in developmental biology research over the past two decades. We now know that a relatively small subset of genes (perhaps 150? 200? 400?) become expressed in [a] the fertilized zygote and/or pluripotent embryonic stem cells, whereas the vast majority of genes are [b] first expressed later during embryogenesis, or during fetogenesis in specific organs/tissues, or in the neonatal period and beyond. The key difference, in my mind, is that AHR is in the former category, whereas steroid receptors (and other successful druggable targets) are in the latter category.

Perhaps it was just serendipity (dumb luck) during my 50+ year career, but my lab stumbled onto the discovery of (not one, but) two such genes in the former category: Ahr (mouse) and AHR (human) and then Slc39a8 (mouse) and SLC39A8 (its human ortholog). Because AHR is expressed in the fertilized zygote and therefore “expressible, as needed” in virtually every cell-type beyond that (i.e. during embryogenesis, fetogenesis, neonatal period and later) — it plays critical “yin-yang” roles in essentially every cell-type and organ [as summarized in table (below) from the 2o17 review]. The same story is still developing (but is probably two decades behind) — for the SLC39A8 (ZIP8) transporter of divalent cations. Therefore, Nancy, to answer your question: any inhibition or overexpression of AHR in one cell-type is VERY likely to perturb AHR regulation in other cell-types (so-called “off-targets”), often leading to undesirable, or lethal, side-effects.

For the sake of grant-writing and discussing in invited reviews, however, it’s always helpful for the Principal Investigator/Author to propose clinical relevance, translational research, and benefitting humankind. These terms bring in more research money in the future.

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