Arsenic-induced differential inflammatory responses in mouse thymus involves NF-κB/STAT-3 disruption, Treg bias and autophagy activation.

Aim: Arsenic contamination in drinking water is a world-wide public health concern. Sustained arsenic ingestion leads to immune alterations and subsequent development of inflammatory and autoimmune diseases; however, the underlying cellular and molecular intricacies of immunotoxicity remains uncharacterized. We aim to understand how exposure to arsenic at different concentrations affects the immune system differentially and whether arsenic-induced differential inflammation dictates altered T-regulatory cell bias and emphasize the role of autophagy in the pathway.

Main Methods: Swiss albino mice were exposed to environmentally relevant concentrations of arsenic in drinking water for 28 days. Examination of thymic cyto-architecture was done to evaluate thymic damage. ELISA was performed for key cytokines. Flow cytometry, western blotting, and immunostaining were performed for cell surface and intracellular proteins. Co-immunoprecipitation and transfection with siRNA were performed to examine the direct physical interactions between proteins.

Key Findings: Our study distinctly demonstrates that arsenic-induced oxidative stress instigates NF-κB activation, which not only provokes pro-inflammatory responses, but also exhibits immune-suppressive activity depending on the dose of arsenic. Co-immunoprecipitation of NF-κBp65 and pSTAT-3 reveals that arsenic alters their physical interaction, thereby suppressing IL-6/STAT-3/IL-17A feedback loop. Flow cytometry and silencing studies demonstrate that NF-κB-driven Treg cell differentiation induces immune-suppression through FoxP3 up-regulation at the highest dose of arsenic and such immune-suppression is actively supported by NF-κB-driven autophagy activation.

Significance: Collectively, our findings reveal that exposure to arsenic differentially impacts the immune system and understanding the molecular cascade might provide direction for prevention/treatment of arsenic-induced inflammatory and autoimmune diseases.