A role for SKN-1/Nrf in pathogen resistance and immunosenescence in caenorhabditis elegans

A proper immune response ensures survival in a hostile environment and promotes longevity. recent evidence indicates that innate immunity,beyond antimicrobial effectors,also relies on host-defensive mechanisms. the caenorhabditis elegans transcription factor skn-1 regulates xenobiotic and oxidative stress responses and contributes to longevity,however,its role in immune defense is unknown. here we show that skn-1 is required for c. elegans pathogen resistance against both gram-negative pseudomonas aeruginosa and gram-positive enterococcus faecalis bacteria. exposure to p. aeruginosa leads to skn-1 accumulation in intestinal nuclei and transcriptional activation of two skn-1 target genes,gcs-1 and gst-4. both the toll/il-1 receptor domain protein tir-1 and the p38 mapk pmk-1 are required for skn-1 activation by pa14 exposure. we demonstrate an early onset of immunosenescence with a concomitant age-dependent decline in skn-1-dependent target gene activation,and a requirement of skn-1 to enhance pathogen resistance in response to longevity-promoting interventions,such as reduced insulin/igf-like signaling and preconditioning h2o2 treatment. finally,we find that wdr-23(rnai)-mediated constitutive skn-1 activation results in excessive transcription of target genes,confers oxidative stress tolerance,but impairs pathogen resistance. our findings identify skn-1 as a novel regulator of innate immunity,suggests its involvement in immunosenescence and provide an important crosstalk between pathogenic stress signaling and the xenobiotic/oxidative stress response. © 2012 papp et al.