Abstract LB-290: Telomere dysfunction is a driver of inflammatory bowel disease

Abstract

Abstract The molecular instigators and therapeutic strategies for inflammatory bowel disease (IBD) are limited. Here, telomere dysfunction is shown to activate pAtm/c-Abl-mediated phosphorylation and stabilization of Yap1 up-regulates pro-IL-18 expression, a major pro-inflammatory factor in IBD. This signaling axis cooperates with gut microbiome which stimulates cytosolic receptors causing activation of caspase-1, which in turn cleaves pro-IL-18 into its mature IL-18 form. Epithelial-derived IL-18 leads to recruitment of IFNγ-secreting T cells and other immunocytes to provoke classical IBD pathology. Consistent with a role for DNA damage signaling as a driver of IBD, newly diagnosed IBD patient samples exhibited elevated expression of pγH2AX, YAP1, Caspase-1 and IL-18 along with significantly reduced telomere lengths compared to healthy tissue controls. Alleviation of IBD pathology can be achieved in mice via telomerase reactivation in intestinal epithelium or pharmacological inhibition of Atm, Yap1, or caspase-1 as well as antibiotic treatment - each intervention dramatically reducing pro-IL-18 cleavage and inflammation. Thus, telomere dysfunction-induced activation of the Atm-Yap1-pro-IL-18 pathway identifies DNA damage signaling as a key instigator and promoter of IBD, illuminating several novel therapeutic strategies for disease interception and management. Note: This abstract was not presented at the meeting. Citation Format: Deepavali Chakravarti, Asha Multani, Prasenjit Dey, Baoli Hu, Di Zhao, Kyle Chang, Mao Xizeng, Guocan Wang, Christoper Terranova, Wen-ting Liao, Denise Spring, Pingping Hou, Jianhua Zhang, Pablo Okhuysen, Eduardo Vilar, Mary K. Estes, Sarah blutt, Alan Wang, Ronald DePinho. Telomere dysfunction is a driver of inflammatory bowel disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-290.