Dysregulation in p38 signalling contributes to altered phenotype and function in Nrf2 deficient dendritic cells (P5025)

Abstract

Abstract Nrf2 is a redox sensitive transcription factor vital for the maintenance of cellular homeostasis. Dendritic cells (DCs) are potent APCs responsible for the initiation of an immune response. Our previous study highlights the role of Nrf2 in DC function (increased costimulatory receptors expression and T cell stimulatory capacity) and intracellular signaling (such as ROS, NFκB and MAPKs). The p38 MAPK pathway plays a pivotal role in the up regulation of costimulatory receptors (CD86 & MHC II). However, it is unclear how Nrf2 affects the integrity of this pathway. In the current study using bone marrow-derived immature DCs from Nrf2 deficient (KO) and wild type mice, we investigate the effect of Nrf2 on various signaling events in the p38 pathway and associated functional responses. Our results indicate that the loss of Nrf2 in DCs resulted in elevated basal p38 phosphorylation. Furthermore, an increase in basal phosphorylation of CREB and ATF-1 - downstream targets of p38, was also observed. This was coupled with increased IL-10 cytokine production at basal conditions and also upon exposure to LPS. Increased costimulatory receptor expression, antigen specific T cell activation propensity and LPS stimulated IL-10 production observed in the KO DCs can be reversed by pharmacological inhibition of p38. These results suggest that deficiency of Nrf2 in DCs leads to dysregulation of the p38 signaling pathway contributing to the altered phenotype and function of these DCs.