Interaction between smoking and ATG16L1T300A triggers Paneth cell defects in Crohn’s disease
Year: 2018
Type: article
Abstract: It is suggested that subtyping of complex inflammatory diseases can be based on genetic susceptibility and relevant environmental exposure (G+E). We propose that using matched cellular phenotypes in human subjects and corresponding preclinical models with the same G+E combinations is useful to this end. As an example, defective Paneth cells can subtype Crohn's disease (CD) subjects; Paneth cell defects have been linked to multiple CD susceptibility genes and are associated with poor outcome. We hypothesized that CD susceptibility genes interact with cigarette smoking, a major CD environmental risk factor, to trigger Paneth cell defects. We found that both CD subjects and mice with ATG16L1T300A (T300A; a prevalent CD susceptibility allele) developed Paneth cell defects triggered by tobacco smoke. Transcriptional analysis of full-thickness ileum and Paneth cell-enriched crypt base cells showed the T300A-smoking combination altered distinct pathways, including proapoptosis, metabolic dysregulation, and selective downregulation of the PPARγ pathway. Pharmacologic intervention by either apoptosis inhibitor or PPARγ agonist rosiglitazone prevented smoking-induced crypt apoptosis and Paneth cell defects in T300A mice and mice with conditional Paneth cell-specific knockout of Atg16l1. This study demonstrates how explicit G+E can drive disease-relevant phenotype and provides rational strategies for identifying actionable targets.
DOI: 10.1172/jci120453
Language: English
Topic: Inflammatory Bowel Disease
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
Funders: Leona M. and Harry B. Helmsley Charitable Trust, Crohn's and Colitis Foundation, National Institutes of Health, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences
Awards: Preclinical Development of an Anti-Mucus Drug, IBD: Role of Genetic and Immunopathologic Mechanisms, Role of virus-receptor interactions in determining norovirus tropism and pathogenesis in vivo, PARP9-DTX3L Control Of Viral Infection and Airway Disease, DEFINING OF CROHN'S DISEASE SUBTYPES USING GENETICS AND METAGENOMICS, IL-33 AND EXCESS MUCUS PRODUCTION, INTERFERON SIGNAL ENHANCERS AS ANTIVIRAL THERAPEUTICS, DEFINING THE BASIS OF EPITHELIAL DEFECTS IN CROHN'S DISEASE PATIENTS, G6796664046, Washington University Institute of Clinical and Translational Sciences, Nod2: A Susceptibility Gene for Crohn's Disease, G8242737674, G9000115080, G9000267277, G9000319192, Determining genomic and host-environment contributions to IBD phenotypes, Washington University Institute of Clinical and Translational Sciences, Cancer Center Support Grant
OpenAlex ID: W2888700516