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

Lu, QiongxuanUmeå universitet,Umeå centrum för molekylär medicin (UCMM),Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM),Umeå Centre for Microbial Research (UCMR),Changchun Chen (author)

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 inC. elegans. Our analysis reveals that NHR-49, theC. elegansortholog of human PPARα 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 theC. elegansortholog of NF-κB inhibitor NFKI-1/IκBζ 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/IκBζ 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-κB, and provides mechanistic insight into the pathogenesis of abnormal IL-17 secretion.

Vladareanu, IoanaUmeå universitet,Umeå centrum för molekylär medicin (UCMM),Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM),Umeå Centre for Microbial Research (UCMR)(Swepub:umu)iovl0001 (author)
Zhao, Lina,1990-Umeå universitet,Umeå centrum för molekylär medicin (UCMM),Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM),Umeå Centre for Microbial Research (UCMR),Changchun Chen(Swepub:umu)lizh0020 (author)
Nilsson, LarsUmeå universitet,Umeå centrum för molekylär medicin (UCMM),Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM),Umeå Centre for Microbial Research (UCMR)(Swepub:umu)lani0001 (author)
Henriksson, JohanUmeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten),Molekylär Infektionsmedicin, Sverige (MIMS),Umeå Centre for Microbial Research (UCMR)(Swepub:umu)johe6219 (author)
Chen, ChangchunUmeå universitet,Umeå centrum för molekylär medicin (UCMM),Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM),Umeå Centre for Microbial Research (UCMR)(Swepub:umu)chch0005 (author)
Umeå universitetUmeå centrum för molekylär medicin (UCMM) (creator_code:org_t)

By the author/editor: Lu, Qiongxuan; Vladareanu, Ioan ...; Zhao, Lina, 1990 ...; Nilsson, Lars; Henriksson, Joha ...; Chen, Changchun

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Neurosciences

NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Biochemistry and ...

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