An Overview of the Advantages of KEAP1-NRF2 System Activation During Inflammatory Disease Treatment.

SIGNIFICANCE: Inflammation can be defined as a protective immune response against harmful exogenous and endogenous stimuli. Nevertheless, prolonged or autoimmune inflammatory responses are likely to cause pathological states that are associated with a production of inflammation-associated molecules along with reactive oxygen species (ROS). Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 (KEAP1-NRF2) signaling provides a cell protection mechanism against oxidative insults when endogenous stress defense mechanisms are imbalanced. Understanding the roles of the KEAP1-NRF2 system in inflammation caused by various types of stimuli may aid in the development of new therapies. Recent Advances: There have been tremendous advances in understanding the mechanism by which the KEAP1-NRF2 pathway abrogates inflammation. In addition to the well-established ROS-dependent pathway, recent studies have provided evidence of the direct repression of the transcription of pro-inflammatory cytokine genes, such as IL1b and IL6 (encoding Interleukin-1β and Interleukin-6, respectively). Further, the expanding functions of NRF2 have elicited interest in the development of therapeutic modalities for inflammatory diseases, including multiple sclerosis and sickle cell disease. Critical Issues and Future Directions: Despite progress in the understanding of molecular mechanisms supporting the roles that NRF2 plays during inflammation, the relationship between NRF2 and other transcription factors and mediators of inflammation still remains ambiguous. Further studies are required to address the effects of functional polymorphisms in KEAP1 and NRF2 that modify susceptibility to specific disease-related inflammation. Comprehensive analyses in the future should explore tissue- or cell-type specific NRF2 activation to elaborate effects of NRF2 induction. Antioxid. Redox Signal. 00, 000-000.