Methyl group donor reduces the Caffeine hippocampal anti-inflammatory effects and potentiates the LPS effect by positive transcription of the Nrf2/Txn1/Nlrp3 axis

Abstract

Nrlp3 inflammasome activation is closely related to the Nrf2/Txn1/Nlrp3 axis, since nod-like receptor 3 (NLRP3) has a critical role through interaction with thioredoxin-interacting protein (TXNIP), which upon dissociating from the Trx1/TXNIP complex and interacting with Nrlp3, promotes the activation of the complex. In this context, nuclear factor erythroid 2-related factor 2 (Nrf2) plays a critical role and can inhibit the activation of the inflammasome. Therefore, the objective of this study was to investigate in inflammatory conditions induced by LPS in vivo and in vitro whether the neuroprotective effect of caffeine would be mediated by the Nrf2/Txn1/Nlrp3 axis. Here, we demonstrate using an in vivo model of neuroinflammation induced by i.p. injection of LPS (0.33 mg/kg) that the reduction in Nrf2 expression and the increase in Nrlp3 and Txn1 expression promoted by LPS were significantly prevented and/or reversed by pre-treatment with caffeine without a direct involvement of epigenetic mechanisms. Furthermore, in vitro results revealed a pro-inflammatory effect for treatment with the CH3 donor (SAM) and an anti-inflammatory effect for the Dnmt inhibitor, RG108. Thus, the joint analysis of the results allows us to conclude that the neuroprotective effect of caffeine observed by the negative modulation of the pro-inflammatory genes, Nlrp3/Txn1, and positive modulation of Nfr2, may be mediated by underlying molecular mechanisms sensitive to positive modulation and/or or negative activation of DNMTs enzymes. We emphasize that additional studies are needed to elucidate the involvement of DNMTs in caffeine-mediated neuroprotection.