ArticleProceedings of the National Academy of Sciences of the United States of America2021
Telomere dysfunction instigates inflammation in inflammatory bowel disease.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 49 citations in OpenAlex.
- Tripartite Interplay of Epithelial, Immune, and Microbiota Dysregulation in Crohn's Disease: Mechanisms and Translational Strategies.Immunity, inflammation and disease · 2026Review
- The ageing holobiont: crosstalk between telomere dynamics, oxidative stress and the gut microbiome.Biological reviews of the Cambridge Philosophical Society · 2026Review
- Relative Leukocyte Telomere Length Is Associated with Multimorbidity Burden in Older Adults: Evidence for Sex-Specific Associations.International journal of molecular sciences · 2026Article
- Multivariable genome-wide analysis elucidates the shared genetic architecture, immunosenescence features, and gut-origin therapeutic targets of ulcerative colitis-associated multisystem inflammation.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Article
- Telomerase Knockout in Myeloid Cells Predisposes Mice to Foam Cell Formation, Dyslipidemia, Lung Fibrosis, and Cardiac Dysfunction.Aging cell · 2026Article
- Immunosenescence and organoids: pathophysiology and therapeutic opportunities.Immunity & ageing : I & A · 2025Review
- Evolutionarily conserved role of telomerase reverse transcriptase in programming the microenvironment via regulation of the cGAS-STING pathway.Nature cell biology · 2025Article
- Loss of Ten1 in mice induces telomere shortening and models human dyskeratosis congenita.Science advances · 2025Article
- Review
- Modification of the telomerase gene with human regulatory sequences resets mouse telomeres to human length.Nature communications · 2025Article
- Cellular senescence defining the disease characteristics of Crohn's disease.Frontiers in immunology · 2025Article
- A living organoid biobank of patients with Crohn's disease reveals molecular subtypes for personalized therapeutics.Cell reports. Medicine · 2024Article
- From Crypts to Cancer: A Holistic Perspective on Colorectal Carcinogenesis and Therapeutic Strategies.International journal of molecular sciences · 2024Review
- Article
- Endothelial-specific telomerase inactivation causes telomere-independent cell senescence and multi-organ dysfunction characteristic of aging.Aging cell · 2024Article
- Challenges and opportunities in inflammatory bowel disease: from current therapeutic strategies to organoid-based models.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2024Review
- YAP represses intestinal inflammation through epigenetic silencing of JMJD3.Clinical epigenetics · 2024Article
- Humanization of the mouseResearch square · 2024Article
- Rapid Remission With Upadacitinib in a Child With Refractory Crohn's Disease andCurrent therapeutic research, clinical and experimental · 2024Article
- Article
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Authors and funding
29 authors at 5 institutions in 2 countries.
Funding
Abstract
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.
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