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

Abstract

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.

Keywords: COVID-19; SARS-CoV-2; acetyl-CoA; aryl hydrocarbon receptor; cancer; immune; melatonin; mitochondria; racism; treatment.

Figure 1

Pro-inflammatory cytokines decrease melatonin and increase gut permeability/dysbiosis, which contributes to immune dysregulation. Pro-inflammatory cytokines also increase indoleamine 2,3-dioxygenase (IDO), leading to kynurenine activation of the aryl hydrocarbon receptor (AhR). This potentiates the initial ‘cytokine storm’ and inhibits the endogenous anti-viral response, via the suppression of mitochondrial function, melatonin, acetyl-coenzyme A (CoA), and specialized pro-resolving mediators (SPMs). Stress, including racial discrimination stress, and pre-existent medical conditions prime and potentiate an elevated pro-inflammatory cytokine response, including via elevated kynurenine activation of the AhR.

Figure 2

AhR activation by air pollutants, kynurenine or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) regulates viral entry, including via SLC6A19 gene activation and B0AT1 induction. B0AT1 forms a dimer with the ACE2r which stabilizes the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) virus and greatly potentiates viral entry. Other dimers/partners of the ACE2r may form a similar function, including TMPRSS2 in the lung. The ACE2r and its partners require to be within lipid rafts, where the presence and/or activation of the α7nAChR in rafts inhibits viral entry. The putative beneficial effects of nicotine against viral entry seem mediated by an increase the levels and activation of the α7nAChR. Ageing, pre-existent medical conditions and AhR activation inhibit melatonin, thereby suppressing the melatonin induction of the α7nAChR. AhR activation, like melatonin, may suppress viral entry by decreasing viral entry via another receptor (lung DDP4).

Figure 3

AhR activation contributes to alterations in mitochondrial metabolism as does suppressed pineal melatonin. By increasing CYP1B1 and suppressing 14-3-3, AhR activation lowers mitochondrial and cytoplasmic melatonin, thereby decreasing sirtuins and superoxide dismutase (SOD)2, contributing to suboptimal mitochondrial function. The decrease in circadian pineal melatonin in the aged, as well as from increased cytokines and gut permeability, lowers Bmal1 induction, which is crucial to upregulating pyruvate dehydrogenase complex (PDC) and its conversion of pyruvate to acetyl-CoA. Acetyl-CoA is a necessary co-substrate of AANAT and therefore for the initiation of the melatonergic pathway. The release of melatonin by cells of the ‘cytokine storm’ is necessary for their switch to a quiescent/phagocytic phenotype and this seem co-ordinated with SPMs induction. Acetyl-CoA is necessary for optimized oxidative phosphorylation (OXPHOS) and tricarboxylic acid (TCA) cycle ATP production. Acetyl-CoA also inhibits the COX2/PGE2/EP4 pathway that underpins exhaustion and is necessary for the increase in glycolysis that is required for anti-viral cells to become activated. The AhR and pineal melatonin act to regulate immune cell metabolism, activity and response to viral infection.

Figure 4

Stress increases hypothalamic and amygdala corticotropin-releasing hormone (CRH) release, thereby activating mucosal mast cells to release tumour necrosis factor (TNF) α, which increases gut permeability/dysbiosis. This leads to an increase in the toll-like receptor (TLR) 4 agonists lipopolysaccharide (LPS) and high-mobility group box (HMGB) 1, which decrease pineal melatonin production, thereby dysregulating the circadian regulation of optimized immune cell function. Decreased butyrate will also lower melatonin and acetyl-CoA production as well as contributing to suboptimal mitochondrial function. Stress, partly by increasing gut permeability/dysbiosis and pro-inflammatory cytokines, leads to an increase in the conversion of tryptophan to kynurenine, thereby lowering serotonin, N-acetylserotonin (NAS), and melatonin levels. Stress, in its many manifestations, is therefore intimately linked to pathways pertinent to the regulation of SARS-CoV-2 severity/fatality.

Figure 5

AhR activation and heightened Aβ levels in the elderly will contribute to platelet activation via decreased melatonin and upregulation of microRNA (miR)-155 and the S1P3r/RhoA/ROCK pathway. The resultant increase in coagulation, thrombin and new embolism formation contribute to SARS-CoV-2 severity/fatality. Racial discrimination stressors may contribute to such processes, given the heightened association of embolism-linked fatalities in African-American deaths during surgery for other types of medical conditions.

Figure 6

AhR-induced cyclooxygenase (COX) 2/PGE2/EP4 has differential effects in anti-viral cells vs. cells of the ‘cytokine storm’. Levels of acetyl-CoA may be significant determinants of AhR effects via the COX2/PGE2/EP4 pathway via acetyl-CoA using sphingosine from sphingosine kinase (SphK) to produce N-acetyl-sphingosine (N-ASph), which, like aspirin, acetylates and inhibits COX2. Acetyl-CoA, as a co-substrate for AANAT, also increases melatonin, which also inhibits this AhR-driven pathway. As such, acetyl-CoA may act to co-ordinate N-ASph and melatonin production and effects, with their differential consequences in NK cells and CD8+ t cells vs. macrophages, neutrophils, and mast cells. This would suggest that variations in acetyl-CoA in these cells will determine their differential activation in SARS-CoV-2 infection, as well as in cancers. The suppression of melatonin by the AhR in all of these cell types will contribute to their dysregulation in SARS-CoV-2 infection, whilst the suppression of pineal melatonin, via a decrease in Bmal1-induced PDC and therefore acetyl-CoA production, will be important in driving the dysregulated immune response in the aged population as well as in those with high-risk, pre-existent medical conditions. N-ASph can also increase SPMs in macrophages, which, along with autocrine melatonin, switches activated macrophages to a more quiescent phagocytic phenotype.

Figure 7

Racial discrimination is associated with increased basal and induced pro-inflammatory cytokines, driving IDO induction of kynurenine, and thereby leading to AhR activation that acts to increase macrophage and neutrophil inflammatory responses, whilst decreasing anti-viral and anti-cancer cell responses. The increased risk of CVD and embolism induced death in African Americans will be contributed to by AhR priming of immune cells and platelet responses. Racial discrimination increases the risk of deaths across many medical conditions and drives the health disparities that are most documented in the US, in ways that involve such processes. Racial discrimination acts via these processes to increase an array of other medical conditions, including type II diabetes that contribute to suboptimal immune responses to viruses as well as increasing cancer susceptibility. The racial discrimination links to gut permeability/dysbiosis require further investigation but are highly likely to contribute to immune dysregulation, given the increase in pro-inflammatory cytokines arising from racial discrimination stress.