Cited by 601Cell death mechanisms and regulationInflammatory Bowel DiseaseNF-κB Signaling Pathways

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FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation

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Welz, Patrick-Simon, Wullaert, Andy, Vlantis, Katerina, Kondylis, Vangelis, Fernández-Majada, Vanesa, Ermolaeva, Maria, Kirsch, Petra, Sterner-Kock, Anja, van Loo, Geert, Pasparakis, Manolis·2011·Nature

DOI 10.1038/nature10273

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Abstract

Intestinal immune homeostasis depends on a tightly regulated cross talk between commensal bacteria, mucosal immune cells and intestinal epithelial cells (IECs). Epithelial barrier disruption is considered to be a potential cause of inflammatory bowel disease; however, the mechanisms regulating intestinal epithelial integrity are poorly understood. Here we show that mice with IEC-specific knockout of FADD (FADD(IEC-KO)), an adaptor protein required for death-receptor-induced apoptosis, spontaneously developed epithelial cell necrosis, loss of Paneth cells, enteritis and severe erosive colitis. Genetic deficiency in RIP3, a critical regulator of programmed necrosis, prevented the development of spontaneous pathology in both the small intestine and colon of FADD(IEC-KO) mice, demonstrating that intestinal inflammation is triggered by RIP3-dependent death of FADD-deficient IECs. Epithelial-specific inhibition of CYLD, a deubiquitinase that regulates cellular necrosis, prevented colitis development in FADD(IEC-KO) but not in NEMO(IEC-KO) mice, showing that different mechanisms mediated death of colonic epithelial cells in these two models. In FADD(IEC-KO) mice, TNF deficiency ameliorated colon inflammation, whereas MYD88 deficiency and also elimination of the microbiota prevented colon inflammation, indicating that bacteria-mediated Toll-like-receptor signalling drives colitis by inducing the expression of TNF and other cytokines. However, neither CYLD, TNF or MYD88 deficiency nor elimination of the microbiota could prevent Paneth cell loss and enteritis in FADD(IEC-KO) mice, showing that different mechanisms drive RIP3-dependent necrosis of FADD-deficient IECs in the small and large bowel. Therefore, by inhibiting RIP3-mediated IEC necrosis, FADD preserves epithelial barrier integrity and antibacterial defence, maintains homeostasis and prevents chronic intestinal inflammation. Collectively, these results show that mechanisms preventing RIP3-mediated epithelial cell death are critical for the maintenance of intestinal homeostasis and indicate that programmed necrosis of IECs might be implicated in the pathogenesis of inflammatory bowel disease, in which Paneth cell and barrier defects are thought to contribute to intestinal inflammation.

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ZBP1/RIP3-Dependent Necroptosis Plays a Role in Hypoxia-Induced Hepatocyte Death and Contributes to Ischemia-Reperfusion InjuryPreprint
Lin, J., Xu, M., Ji, H., Huang, W., Zhou, Y., Zhou, Y., Liu, Y., Sang, Y., Qian, Y., Gu, J., et al. (2025) · SSRN Electronic Journal · doi:10.2139/ssrn.5136136
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Ketamine protects against sepsis-associated encephalopathy by reverting microglial polarization through suppression of receptor-interacting protein kinase 1-driven signalingPreprint
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Against the RIPK3 Current
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Additional file 1 of RIPK3 activation induces TRIM28 derepression in cancer cells and enhances the anti-tumor microenvironment
Park, H.-H., Kim, H.-R., Park, S.-Y., Hwang, S.-M., Hong, S. M., Park, S., Kang, H. C., Morgan, M. J., Cha, J.-H., Lee, D., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16305850
Additional file 1 of Musashi-2 potentiates colorectal cancer immune infiltration by regulating the post-translational modifications of HMGB1 to promote DCs maturation and migration
Meng, X., Na, R., Peng, X., Li, H., Ouyang, W., Zhou, W., You, X., Li, Y., Pu, X., Zhang, K., et al. (2024) · Figshare · doi:10.6084/m9.figshare.25210502
Additional file 3 of Musashi-2 potentiates colorectal cancer immune infiltration by regulating the post-translational modifications of HMGB1 to promote DCs maturation and migration
Meng, X., Na, R., Peng, X., Li, H., Ouyang, W., Zhou, W., You, X., Li, Y., Pu, X., Zhang, K., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26679974
Additional file 2 of Musashi-2 potentiates colorectal cancer immune infiltration by regulating the post-translational modifications of HMGB1 to promote DCs maturation and migration
Meng, X., Na, R., Peng, X., Li, H., Ouyang, W., Zhou, W., You, X., Li, Y., Pu, X., Zhang, K., et al. (2024) · Figshare · doi:10.6084/m9.figshare.25210846
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c-FLIP as a potent anticancer target : Enhancement of cancer cell apoptosis by compounds identified through virtual screening
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Caractérisation de nouveaux inhibiteurs de la kinase RIPK1 et de la nécroptose
Cann, F. L. (2017) · theses.fr (ABES) · doi:10.70675/14750b73za612z432ezbf7cz5b72ea09e2e5
Emerging small molecules for ulcerative colitis: clinical advancements and trial insights
Lanzotti, C., Fanizzi, F., D’Amico, F., Zilli, A., Furfaro, F., Allocca, M., Solitano, V., Cicerone, C., Massironi, S., Parigi, T. L., et al. (2026) · Expert Opinion on Emerging Drugs · doi:10.1080/14728214.2026.2680722
“…and scaffolding function, takes part in TNF-mediated necroptosis and apoptosis [48–50] as well as in the regulation of NF-κB-mediated inflammation, as seen in some IMIDs such as rheumatoid arthritis, ankylosing spondylitis, psoriasis [51], and IBD, as evidenced by studies conducted in mice [52,53].”
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“Mice with an intestinal epithelial cell-specific FADD deficiency (FADD IEC-KO ) develop spontaneous colitis and ileitis, characterized by epithelial hyperplasia, ulcerating lesions, Paneth cell loss, and robust immune cell infiltration – all of which stem from aberrant RIPK3 activation [86].”
Sorafenib Restores Pentose Phosphate Pathway‐Related Redox Homeostasis via the c‐Raf/HSP90/G6PD Axis in Hepatic Ischemia‐Reperfusion Injury
Gao, F., Dong, L., Tan, Y., Zhang, Z., Xu, S., Lou, Z., Wu, Y., Chen, S., Zhuang, L., Lian, Z., et al. (2026) · MedComm · doi:10.1002/mco2.70819
“In vivo experiments have also shown that middle-dose sorafenib protects against tumor necrosis factor-induced systemic inflammatory response syndrome and renal IRI [ 24, 25 ].”
MIT-001, a Mitochondria-Targeted ROS Scavenger, Ameliorates DSS-Induced Colitis and Is Associated with Reduced HMGB1 and IL-1β Expression
Kim, D., Kim, S. H., Choe, J. W., Kim, S. Y., Hyun, J. J., Jung, S. W., Jung, Y. K., Yim, H. J., & Koo, J. S. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27136051
“…studies have demonstrated that necroptosis of intestinal epithelial cells can induce intestinal inflammation resembling that observed in IBD [9,10], and increased expression of key necroptosis mediators, including receptor-interacting protein kinase 3 (RIPK3) and mixed-lineage kinase…”
Receptor interacting protein kinase 1 as a potential therapeutic target in inflammatory bowel disease: biological rationale and emerging clinical evidence
Honap, S., Dignass, A. U., Jairath, V., Magro, F., Danese, S., & Peyrin‐Biroulet, L. (2026) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2026.2717160
“Similarly, mice lacking FADD in the intestinal epithelium develop spontaneous epithelial necrosis, Paneth cell loss, and marked intestinal inflammation, which is rescued by concurrent deletion of RIPK3 [20].”
BindingDB Entry 50049028: Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases.
BindingDB (2019) · UC San Diego · doi:10.7270/q2sq92nr
BindingDB Entry 50043782: TBA
BindingDB (2014) · UC San Diego · doi:10.7270/q2c24xw2
BindingDB Entry 50013742: Ring closure strategy leads to potent RIPK3 inhibitors.
BindingDB (2022) · UC San Diego · doi:10.7270/q2kp85x0
BindingDB Entry 50014959: Discovery and Structure-Based Optimization of Fragments Binding the Mixed Lineage Kinase Domain-like Protein Executioner Domain.
BindingDB (2023) · UC San Diego · doi:10.7270/q2zc86rg

Authors: Welz, P.-S., Wullaert, A., Vlantis, K., Kondylis, V., Fernández-Majada, V., Ermolaeva, M., Kirsch, P., Sterner-Kock, A., van Loo, G., & Pasparakis, M.
Affiliations: University of Cologne (DE)
Universität Ulm (DE)
Corresponding author: Pasparakis, Manolis
ORCID: Welz, Patrick-Simon
Wullaert, Andy
Vlantis, Katerina
Kondylis, Vangelis
Ermolaeva, Maria
Pasparakis, Manolis
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2011-07-31
Volume: 477
Issue: 7364
Pages: 330-334
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature10273
OpenAlex: W1988848002
Cited by: 594
References: 36
Citations by year: 2026: 7 · 2025: 28 · 2024: 34 · 2023: 28 · 2022: 37 · 2021: 45 · 2020: 37 · 2019: 31 · 2018: 28 · 2017: 42 · 2016: 57 · 2015: 44 · 2014: 81 · 2013: 51 · 2012: 33
FWCI: 22.96
Type: journal article
Language: en
Open access: green
zenodo.org
Licence: other-oa
www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Ghent University Academic Bibliography (Ghent University) (submittedVersion)
Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, other-oa)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
Keywords: FADD, RIPK3, necroptosis, epithelial cell necrosis, intestinal inflammation, Paneth cells, caspase-8, TNF-α, CYLD, NEMO, Toll-like receptor signaling, microbiota, Crohn's disease, intestinal epithelial cells, immune homeostasis, colitis, MyD88, commensal bacteria
MeSH terms: Deubiquitinating Enzyme CYLD, Animals, Chronic Disease, Colitis, Colon, Cysteine Endopeptidases, Enteritis, Epithelial Cells, Necrosis, Inflammatory Bowel Diseases, Signal Transduction, Apoptosis, Paneth Cells, Intracellular Signaling Peptides and Proteins, Tumor Necrosis Factors, Mice, Fas-Associated Death Domain Protein, Receptor-Interacting Protein Serine-Threonine Kinases, Myeloid Differentiation Factor 88, Metagenome

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FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation

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