IL-17 activation undermines longevity and stress tolerance by inhibiting a protective transcriptional network

Abstract

Aberrant cytokine secretion contributes to the pathogenesis of autoimmune diseases and age-related disorders, but the molecular mechanism underlying this is not entirely clear. Here, we elucidate how interleukin-17 (IL-17) overactivation shortens lifespan and damages defense mechanisms against stress in C. elegans. Our analysis reveals that NHR-49, the C. elegans ortholog of human PPAR and HNF4, is the central component in the transcriptional network undermined by increased IL-17 signaling. Both NHR-49 and its coactivator MDT-15 physically interact with the downstream components of IL-17 pathway, and their expression is significantly decreased when IL-17 signaling is enhanced. IL-17 overactivation also induces the expression and nucleus entry of the C. elegans ortholog of NF-{kappa}B inhibitor NFKI-1/I{kappa}B{zeta} to repress the activity of transcriptional coactivator MDT-15 and CBP-1. IL-17 signaling acts on neurons to modulate the activity of NFKI-1/I{kappa}B{zeta} and NHR-49. In addition, persistent IL-17 activation decreases the expression of HLH-30/TFEB, leading to the reduced transcription of lysosomal lipase genes in the distal tissues. All these jointly contribute to the increased sensitivity to oxidative stress of animals with enhanced IL-17 signaling. Collectively, our work illustrates a transcription system undermined by IL-17 overactivation in the animals without NF-{kappa}B, and provides mechanistic insight into the pathogenesis of abnormal IL-17 secretion.