Telomere dysfunction activates YAP1 to drive tissue inflammation

Inflammatory bowel disease (IBD) is a challenging condition with limited therapeutic options. Inflammasome activation is integral to IBD pathogenesis, although the molecular instigators of its activation remain obscure. Here, we establish that telomere dysfunction activates the Yap1 transcriptional co-activator through pATM/c-Abl, which up-regulates expression of microbial receptors Nlrc4 and Nlrc5 and the cytokine pre-IL-18. Microbial engagement of these cytosolic receptors leads to production of mature IL-18, recruiting T cells and other immunocytes which secrete IFN-gamma to drive classical IBD pathology. Genotoxic stress per se (ionizing radiation) can also drive inflammasome activation. Alleviation of IBD pathology can be achieved via telomerase reactivation in intestinal epithelium, antibiotic treatment or pharmacological inhibition of Yap1 - reducing Nlrc4/5 expression as well as IL-18 and IFN-gamma production. Thus, telomere dysfunction-induced inflammasome activation identifies DNA damage signaling as a key instigator and promoter of IBD, illuminating potential novel therapeutic strategies for prevention and disease management. Overall design: Total RNA profiles from large intestinal GFPsorted CBC cells and unsorted crypt epithelial cells from mTert heterozygous mice and mTert null mice generation 3 and 4 and telomerase reactivated epithelial cells from generation 4 mice