NRF2: sensing stress, shaping immunity - keeping inflammation quiet and antigens out of sight

Abstract

The Cap ‘n’ Collar basic leucine zipper transcription factor NRF2 has been linked to inflammation almost since its identification as the master regulator of oxidative stress responses. Early studies demonstrated systemic inflammation and dysregulated immune responses following NRF2 loss. Initially, NRF2 was thought to regulate pro-inflammatory genes primarily through its antioxidant function, by binding to antioxidant response elements. However, studies by Kobayashi et al. revealed that, in LPS-treated murine macrophages, NRF2 binds to a non-ARE sequence near the Il6 and Il1b genes, where it regulates RNA polymerase II recruitment and represses pro-inflammatory gene transcription. More recent findings have further expanded the role of NRF2 in regulating immune and inflammatory responses by demonstrating that NRF2 suppresses transcription of the MHC class II transactivator ( CIITA ), a master regulator of major histocompatibility complex class II expression and antigen presentation. This article provides an overview of the historical evidence linking NRF2 to inflammatory conditions and discusses the emerging role of NRF2 in the transcriptional control of pro-inflammatory cytokines and CIITA . The molecular mechanisms through which NRF2 regulates Il6 , Il1b , and CIITA remain incompletely understood and may involve yet-unidentified transcriptional co-regulators, which will be explored in this review.