Hypothesis: Emerging Roles for Aryl Hydrocarbon Receptor in Orchestrating CoV-2-Related Inflammation

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.