AhR Participates in COVID-19’s Immune-Inflammatory Imbalance

The comprehension of AhR’s role in the COVID-19 framework must consider its participation in human physiology and, in particular, in inflammatory and immune processes, where AhR is involved in the regulation of both innate and adaptive immunity, as it influences both DCs and T lymphocytes. In DCs, it decreases the expression of the Major Histocompatibility Complex II (MHC II). It also regulates the production of inflammatory cytokines, such as IL-6, IL12, IL15, and IL18, which are usually produced during DC differentiation. DCs differentiation takes place upon their exposure to T cells, viral/bacterial components or pro-inflammatory molecules, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), IFNα, and inflammatory cytokines such as IL-6 and TNFα. This point is of pivotal importance, due to the crosstalk between several inflammatory molecules such as IL-6, TNFα and the AhR pathway. This interplay also reverberates on the differentiation of Th17 and Treg, in particular in type 1 regulatory T cell (TR1) stabilization. AhR can deeply affect T cells metabolism, which can be modulated depending on the AhR ligand. It has been demonstrated that the differentiation of TR1 cells is the result of the sequential collaboration of Hypoxia Inducible Factor-1α (HIF-1α) and AhR. In physiologic settings, AhR endows the degradation of HIF-1α, while in inflammation, which is frequently associated with hypoxia, HIF-1α inactivates AHR, thus interfering with TR1 cell differentiation. AhR is also abundantly expressed in DCs.