Arsenic-induced dose-dependent modulation of the NF-κB/IL-6 axis in thymocytes triggers differential immune responses

•We for the first time explicitly show that arsenic exposure causes morphological damage to the thymus and results in heightened death of thymocytes.•Our data suggests that arsenic-induced apoptosis occurs due to increase in cellular oxidative and nitrosative stress.•We have for the first time established a non-classical role of NF-κB, correlating it with increase in FoxP3 expression.•The % of CD4+ CD25+ T cells were high and expression of FoxP3 has also increased at higher doses of arsenic indicating an nTreg bias.

Arsenic contamination of drinking water is a matter of global concern. Arsenic intake impairs immune responses and leads to a variety of pathological conditions including cancer. In order to understand the intricate tuning of immune responses elicited by chronic exposure to arsenic, a mouse model was established by subjecting mice to different environmentally relevant concentrations of arsenic in drinking water for 30 days. Detailed study of the thymus, a primary immune organ, revealed arsenic-mediated tissue damage in both histological specimens and scanning electron micrographs. Analysis of molecular markers of apoptosis by Western blot revealed a dose-dependent activation of the apoptotic cascade. Enzymatic assays supported oxidative stress as an instigator of cell death. Interestingly, assessment of inflammatory responses revealed disparity in the NF-κB/IL-6/STAT3 axis, where it was found that in animals consuming higher amounts of arsenic NF-κB activation did not lead to the classical IL-6 upregulation response. This deviation from the canonical pathway was accompanied with a significant rise in numbers of CD4+ CD25+ FoxP3 expressing cells in the thymus. The cytokine profile of the animals exposed to higher doses of arsenic also indicated an immune-suppressed milieu, thus validating that arsenic shapes the immune environment in context to its dose of exposure and that at higher doses it leads to immune-suppression. Our study establishes a novel role of arsenic in regulating immune homeostasis in context to its dose, where, at higher doses, arsenic related upregulation of NF-κB cascade takes on an alternative role that is correlated with increased immune-suppression.