Aryl hydrocarbon receptor engagement during redox alteration determines the fate of CD4⁺ T cells in C57BL/6 mice

Abstract

The preservation of the redox homeostasis is critical for cell survival and functionality. Redox imbalance is an essential inducer of several pathological states. CD4+/helper T cells are highly dependent on the redox state of their surrounding milieu. The potential of the aryl hydrocarbon receptor (AhR) engagement in controlling CD4+ T‐cell fate during redox alteration is still challenging. C57BL/6 mice were treated with AhR agonist 6‐formylindolo[3,2‐b]carbazole (FICZ), AhR antagonist CH223191, an inhibitor of glutathione biosynthesis buthionine sulfoximine (BSO), and the antioxidant N‐acetylcysteine (NAC) alone or in combination. Six days later, splenocytes were evaluated for the expression of the redox‐related genes and the possible changes in T‐cell subsets. FICZ like BSO significantly elevated the expression of HMOX1, GCLC, and GCLM genes but it failed to increase the expression of the Nrf2 gene. Moreover, FICZ + BSO increased while FICZ + CH223191 or NAC decreased the expression of these genes. FICZ also significantly increased Th1 cell numbers but decreased Tregs in a dose‐dependent manner. Furthermore, a high dose of FICZ + CH223191 + NAC significantly enhanced Th1, Th17, and Treg cells but its low dose in such a situation increased Th2 and Th17 while decreased Treg cells. AhR engagement during redox alteration can determine the fate of CD4 + T cells, so, AhR agonists or antagonists might be useful in assessing immune responses. However, these results need further verifications in vitro and in animal models of various diseases.

Pharmacological blockage of the AHR-CYP1A1 axis: a call for in vivo evidence

“…Replacing NAC for BSO in the latter scenario increased Th1 and Th17 cells. Such results led to the conclusion that AHR activation interferes with the fate of T cells, influenced by redox alterations [ 82 ].…”

PHGDH knockdown increases sensitivity to SR1, an aryl hydrocarbon receptor antagonist, in colorectal cancer by activating the autophagy pathway

“…AhR influences the major stages of tumorigenesis-initiation, promotion, progression and metastasis [20]. Metabolites in the tumor microenvironment can affect T cell proliferation and function, as well as the activation of AhR ligands, and were identified as important for the differentiation and activation of T helper 2 and T helper 17 cells, regulatory T cells, and dendritic cells [21,22]. Despite decades of research, the full function of the AhR pathway has yet to emerge.…”