Year: 2017
Type: article
Abstract: is associated with Crohn's disease, an inflammatory bowel disease (IBD), and poor survival in allogeneic hematopoietic stem cell transplant recipients. We demonstrate that ATG16L1 in the intestinal epithelium is essential for preventing loss of Paneth cells and exaggerated cell death in animal models of virally triggered IBD and allogeneic hematopoietic stem cell transplantation. Intestinal organoids lacking ATG16L1 reproduced this loss in Paneth cells and displayed TNFα-mediated necroptosis, a form of programmed necrosis. This cytoprotective function of ATG16L1 was associated with the role of autophagy in promoting mitochondrial homeostasis. Finally, therapeutic blockade of necroptosis through TNFα or RIPK1 inhibition ameliorated disease in the virally triggered IBD model. These findings indicate that, in contrast to tumor cells in which autophagy promotes caspase-independent cell death, ATG16L1 maintains the intestinal barrier by inhibiting necroptosis in the epithelium.
DOI: 10.1084/jem.20170558
Institutions: New York University, Memorial Sloan Kettering Cancer Center, NYU Langone Health, GlaxoSmithKline (United States), Rutgers, The State University of New Jersey, Rutgers New Jersey Medical School, University of Rochester Medicine, University of Rochester, Cornell University, Weill Cornell Medicine
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: Howard Hughes Medical Institute, Burroughs Wellcome Fund, Alex's Lemonade Stand Foundation for Childhood Cancer, Stony Wold-Herbert Fund, Lymphoma Foundation, Memorial Sloan-Kettering Cancer Center, Uehara Memorial Foundation, Geoffrey Beene Cancer Research Center, American Society for Blood and Marrow Transplantation, Parker Institute for Cancer Immunotherapy, Mochida Memorial Foundation for Medical and Pharmaceutical Research, National Institutes of Health, Genentech, School of Medicine, New York University, University of California, San Francisco, 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 Research Resources
Awards: G1176657420, G1229558712, G1558408032, G2051006376, G2171762837, G289723095, Mucosal Immunity and Microbiota in Intestinal Graft-versus-Host Disease, Strategies to Enhance Lymphoid Recovery After Radiation-Induced Injury, G3844457025, The role of autophagy gene Atg16L1 in allogeneic hematopoietic stem cell transplantation - Renewal - 1, G5627732322, G6244704152, Strategies to enhance immune reconstitution after bone marrow transplant, G6550837872, Role of Nod2 in preventing intestinal disease downstream of microbial imbalances, G6709037530, IL-22 in Thymic Regeneration, G7665029556, G7929769479, G7985458334, Inverted two photon laser scanning microscope for host defense, Cancer Center Support Grant, Redefining the role of autophagy in bacterial disease, Characterization of a commensal enteric virus, Cancer Center Support Grant, G957729743
OpenAlex ID: W2913465139