The inhibition of TXNRD1 by methylglyoxal impairs the intracellular control of Mycobacterium tuberculosis.

Type 2 diabetes (DM) is a risk factor for development of tuberculosis (TB). Methylglyoxal (MGO), a reactive carbonyl increased during DM targets diverse macromolecules. Here we discovered that MGO converted the mammalian selenoprotein thioredoxin reductase 1 (TXNRD1) to a NADPH oxidase, activating the NRF2 transcription factor in bone marrow macrophages (BMM). NRF2 signaling hampered the production of immune molecules by BMM, thus allowing intracellular growth of M. tuberculosis (Mtb). The overexpression of NRF2 was sufficient to increase the Mtb growth. Several inhibitors of TXNRD1 mimicked the effects of MGO on Mtb growth in BMM. MGO and the TXNRD1 inhibitor auranofin also increased the susceptibility of mice to Mtb infection. Finally, IFN-γ abrogated the MGO-triggered suppression of the protective responses to Mtb in BMM, by epigenetic regulation of immune genes, without impairing NRF2 activation. Thus, metabolic alterations in DM may have a causative role in TB-DM comorbidity, by activating NRF2 responses that impair immune protective responses.