TY - JOUR
T1 - Telomere dysfunction instigates inflammation in inflammatory bowel disease
AU - Chakravarti, Deepavali
AU - Lee, Rumi
AU - Multani, Asha S
AU - Santoni, Andrea
AU - Keith, Zachery
AU - Hsu, Wen-Hao
AU - Chang, Kyle
AU - Reyes, Laura
AU - Rashid, Asif
AU - Wu, Chang-Jiun
AU - Li, Jun
AU - Zhang, Jiexin
AU - Shim, Hong Seok
AU - Chandra, Krishna
AU - Deng, Pingna
AU - Spring, Denise J
AU - Nielsen, Ole Haagen
AU - Riis, Lene Buhl
AU - Mayigegowda, Kavya Kelagere
AU - Blutt, Sarah E
AU - Zhang, Jianhua
AU - Younes, Mamoun
AU - DuPont, Andrew
AU - Thirumurthi, Selvi
AU - Vilar, Eduardo
AU - Estes, Mary K
AU - Colla, Simona
AU - Shroyer, Noah F
AU - DePinho, Ronald A
PY - 2021/7/20
Y1 - 2021/7/20
N2 - Inflammatory bowel disease (IBD) is a chronic inflammatory condition driven by diverse genetic and nongenetic programs that converge to disrupt immune homeostasis in the intestine. We have reported that, in murine intestinal epithelium with telomere dysfunction, DNA damage-induced activation of ataxia-telangiectasia mutated (ATM) results in ATM-mediated phosphorylation and activation of the YAP1 transcriptional coactivator, which in turn up-regulates pro-IL-18, a pivotal immune regulator in IBD pathogenesis. Moreover, individuals with germline defects in telomere maintenance genes experience increased occurrence of intestinal inflammation and show activation of the ATM/YAP1/pro-IL-18 pathway in the intestinal epithelium. Here, we sought to determine the relevance of the ATM/YAP1/pro-IL-18 pathway as a potential driver of IBD, particularly older-onset IBD. Analysis of intestinal biopsy specimens and organoids from older-onset IBD patients documented the presence of telomere dysfunction and activation of the ATM/YAP1/precursor of interleukin 18 (pro-IL-18) pathway in the intestinal epithelium. Employing intestinal organoids from healthy individuals, we demonstrated that experimental induction of telomere dysfunction activates this inflammatory pathway. In organoid models from ulcerative colitis and Crohn's disease patients, pharmacological interventions of telomerase reactivation, suppression of DNA damage signaling, or YAP1 inhibition reduced pro-IL-18 production. Together, these findings support a model wherein telomere dysfunction in the intestinal epithelium can initiate the inflammatory process in IBD, pointing to therapeutic interventions for this disease.
AB - Inflammatory bowel disease (IBD) is a chronic inflammatory condition driven by diverse genetic and nongenetic programs that converge to disrupt immune homeostasis in the intestine. We have reported that, in murine intestinal epithelium with telomere dysfunction, DNA damage-induced activation of ataxia-telangiectasia mutated (ATM) results in ATM-mediated phosphorylation and activation of the YAP1 transcriptional coactivator, which in turn up-regulates pro-IL-18, a pivotal immune regulator in IBD pathogenesis. Moreover, individuals with germline defects in telomere maintenance genes experience increased occurrence of intestinal inflammation and show activation of the ATM/YAP1/pro-IL-18 pathway in the intestinal epithelium. Here, we sought to determine the relevance of the ATM/YAP1/pro-IL-18 pathway as a potential driver of IBD, particularly older-onset IBD. Analysis of intestinal biopsy specimens and organoids from older-onset IBD patients documented the presence of telomere dysfunction and activation of the ATM/YAP1/precursor of interleukin 18 (pro-IL-18) pathway in the intestinal epithelium. Employing intestinal organoids from healthy individuals, we demonstrated that experimental induction of telomere dysfunction activates this inflammatory pathway. In organoid models from ulcerative colitis and Crohn's disease patients, pharmacological interventions of telomerase reactivation, suppression of DNA damage signaling, or YAP1 inhibition reduced pro-IL-18 production. Together, these findings support a model wherein telomere dysfunction in the intestinal epithelium can initiate the inflammatory process in IBD, pointing to therapeutic interventions for this disease.
UR - http://www.scopus.com/inward/record.url?scp=85109879044&partnerID=8YFLogxK
U2 - 10.1073/pnas.2024853118
DO - 10.1073/pnas.2024853118
M3 - Journal article
C2 - 34253611
SN - 0027-8424
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 29
M1 - e2024853118
ER -