NRF2 Plays a Crucial Role in the Tolerogenic Effect of Ethyl Pyruvate on Dendritic Cells.

Abstract

Ethyl pyruvate (EP) is a redox-active compound that has been previously shown to be effective in restraining immune hyperactivity in animal models of various autoimmune and chronic inflammatory diseases. Importantly, EP has also been proven to have a potent tolerogenic effect on dendritic cells (DCs). Here, the influence of EP on the signaling pathways in DCs relevant for their tolerogenicity, including anti-inflammatory NRF2 and pro-inflammatory NF-κB, was explored. Specifically, the effects of EP on DCs obtained by GM-CSF-directed differentiation of murine bone marrow precursor cells and matured under the influence of lipopolysaccharide (LPS) were examined via immunocytochemistry and RT-PCR. EP counteracted LPS-imposed morphological changes and down-regulated the LPS-induced expression of pro-inflammatory mediators in DCs. While it reduced the activation of NF-κB, EP potentiated NRF2 and downstream antioxidative molecules, thus implying the regulation of NRF2 signaling pathways as the major reason for the tolerizing effects of EP on DCs.