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FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation
Open accessAbstract
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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“Along similar lines, the concurrent deletion of Ripk3 averts perturbations of cutaneous and intestinal homeostasis imposed by the tissue-specific ablation of Fadd or Casp8 [483, 487, 488].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [488]
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BackgroundTargeting RIP Kinases in Chronic Inflammatory Disease
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“mia–reperfusion injury (IRI) [38,39], pancreatitis [16,17,40], bowel disease [41,42], inflammation-mediated neurodegenerative dis-”
BackgroundDevelopmental checkpoints guarded by regulated necrosis
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“Mice with intestine-specific ablation of caspase-8, FADD, or RIPK1, survive to birth, but they succumb within the first month and display gross abnormalities of the gut epithelia, providing evidence that both necroptosis and apoptosis are important mediators of cell death in the gut [86–89].”
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“…has been shown to promote IBD development in humans (Gunther et al, 2011; Pierdomenico et al, 2014; Lehle et al, 2019) as well as chronic intestinal inflammation in different mouse models (Gunther et al, 2011; Welz et al, 2011; Wittkopf et al, 2013; Vlantis et al, 2016; Schwarzer et al, 2020).”
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Newton, K., & Gitlin, A. D. (2022) · Biochemical Journal · doi:10.1042/bcj20210735 · Cited by 26
Cobalt Chloride Induces Necroptosis in Human Colon Cancer HT-29 Cells
Wang, H., & Zhang, B. (2015) · Asian Pacific Journal of Cancer Prevention · doi:10.7314/apjcp.2015.16.6.2569 · Cited by 24
“infection, neurodegenerative diseases, auto-immune disorders, as well as ischemia-reperfusion injury, which underscores the crucial role of programmed necrosis in maintaining metazoans stable (Cho et al., 2009; Welz et al., 2011; Zhang et al., 2011; Narayan et al., 2012; Saddoughi et al., 2013).”
BackgroundZhang, C., Luo, Y., He, Q., Liu, S., He, A., & Yan, J. (2019) · Clinical Science · doi:10.1042/cs20181081 · Cited by 26
Necroptotic movers and shakers: cell types, inflammatory drivers and diseases
Weir, A. L., Hughes, S. A., Rashidi, M., Hildebrand, J. M., & Vince, J. E. (2020) · Current Opinion in Immunology · doi:10.1016/j.coi.2020.09.008 · Cited by 22
Necroptosis-Mediated eCIRP Release in Sepsis
Reilly, B., Tan, C., Murao, A., Nofi, C. P., Jha, A., Aziz, M., & Wang, P. (2022) · Journal of Inflammation Research · doi:10.2147/jir.s370615 · Cited by 26
“RIPK3 knockout was proven to effectively mediate the pathological effects of this FADD deficiency.(21) It has been shown that important regulators of necroptotic cell death, RIPK1, RIPK3 and MLKL,”
BackgroundDagenais, M., Dupaul-Chicoine, J., Champagne, C., Skeldon, A. M., Morizot, A., & Saleh, M. (2015) · Mucosal Immunology · doi:10.1038/mi.2015.46 · Cited by 24
Baghdadi, M., Chiba, S., Yamashina, T., Yoshiyama, H., & Jinushi, M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0039607 · Cited by 23
“through TNFR and RIP1/3-mediated antagonism of apoptotic pathways [19–22].”
Multiple ways to die: Non-apoptotic forms of cell death
Tsujimoto, Y. (2012) · Acta Oncologica · doi:10.3109/0284186x.2011.648340 · Cited by 23
Davuluri, K. S., & Chauhan, D. S. (2022) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2022.1009901 · Cited by 25
“These proteins play an important role in apoptosis signaling and are the mediators of non-apoptotic CD95 signaling during T-cell proliferation (Welz et al., 2011).”
BackgroundZhou, B., Xiao, K., Guo, J., Xu, Q., Xu, Q., Lv, Q., Zhu, H., Zhao, J., & Liu, Y. (2024) · Journal of Hazardous Materials · doi:10.1016/j.jhazmat.2024.134601 · Cited by 22
Research Progress on Micro(nano)plastic-Induced Programmed Cell Death Associated with Disease Risks
Liu, H., Li, H., Chen, T., Fan, Y., Lin, Q., Zhao, H., Jin, L., & Peng, R. (2024) · Toxics · doi:10.3390/toxics12070493 · Cited by 23
“In an in vivo mouse genetic model, Welz et al. demonstrated a link between the regulatory mechanism of necroptosis and the pathogenesis of chronic intestinal inflammation in humans [202].”
BackgroundOntogeny of Intestinal Epithelial Innate Immune Responses
Hornef, M. W., & Fulde, M. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00474 · Cited by 26
“Epithelial-specific knockouts that impair cell signaling (28, 38, 39), disturb histone acetylation and microRNA function (56, 57), reduce apoptosis (43), alter epithelial cell differentiation (58, 59) or decrease mucus production (60), and lead to tissue damage and mucosal inflammation.”
BackgroundKatturajan, R., & Prince, S. E. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.119629 · Cited by 20
Wang, Y., Zhang, B., Liu, S., Xu, E., & Wang, Z. (2023) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2023.117373 · Cited by 22
Regulation of Protein Kinase C Inactivation by Fas-associated Protein with Death Domain
Cheng, W., Wang, L., Zhang, R., Du, P., Yang, B., Zhuang, H., Tang, B., Yao, C., Yu, M., Wang, Y., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.342170 · Cited by 21
Life after death: RIP1 and RIP3 move beyond necroptosis
Berger, S., Bertin, J., & Gough, P. C. (2016) · Cell Death Discovery · doi:10.1038/cddiscovery.2016.56 · Cited by 21
The importance of murine phospho-MLKL-S345 in situ detection for necroptosis assessment in vivo
Kelepouras, K., Saggau, J., Varanda, A. B., Zrilić, M., Kiefer, C., Rakhsh-Khorshid, H., Lisewski, I., Uranga-Murillo, I., Arias, M. A., Pardo, J., et al. (2024) · Cell Death and Differentiation · doi:10.1038/s41418-024-01313-6 · Cited by 23
“…colon in fl ammation, by preventing MLKL-induced necroptosis, this is not suf fi cient to prevent ileitis, where it was proposed that Casp8 also drives Gasdermin-D-mediated pyroptosis of FADD-de fi cient intestinal epithelial cells which contributes to the observed in fl ammatory phenotype [35, 67].”
Rübbelke, M., Hamilton, J. Y., Binder, F. P. C., Bauer, M., King, J., Nar, H., & Zeeb, M. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00686 · Cited by 22
Cells and mediators of inflammation as effectors of epithelial repair in the inflamed intestine
Crifò, B., & MacNaughton, W. K. (2021) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00194.2021 · Cited by 19
Tumor necrosis factor is a necroptosis-associated alarmin
Pinci, F., Gaidt, M. M., Jung, C., Nagl, D., Kuut, G., & Hornung, V. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1074440 · Cited by 20
Fn14 and TNFR2 as regulators of cytotoxic TNFR1 signaling
Siegmund, D., Zaitseva, O., & Wajant, H. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1267837 · Cited by 20
Macrophages and Recently Identified Forms of Cell Death
Sanz, A. B., Sánchez-Niño, M. D., Izquierdo, M. C., González–Espinoza, L., Ucero, A. C., Poveda, J., Ruiz‐Andrés, O., Ruiz‐Ortega, M., Selgas, R., Egido, J., et al. (2013) · International Reviews of Immunology · doi:10.3109/08830185.2013.771183 · Cited by 20
“Necroptosis inhibition by genetic or chemical approaches reduces inflammation in lethal systemic inflammatory response syndrome and in chronic intestinal inflammation and improves renal injury induced by ischemia-reperfusion [66,75,76].”
BackgroundTAK1 regulates Paneth cell integrity partly through blocking necroptosis
Simmons, A., Kajino‐Sakamoto, R., & Ninomiya‐Tsuji, J. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.98 · Cited by 20
“epithelial-specific deletion of necroptosis inhibitors such as caspase 8 and its activator Fas-associated protein with death domain (FADD) induces Paneth cells loss.(31,32) This might suggest that Paneth cells are sensitive to necroptosis.”
BackgroundMLKL deficiency inhibits DSS-induced colitis independent of intestinal microbiota
Zhang, J., Qin, D., Yang, Y., Hu, G., Qin, X., Du, C., & Chen, W. (2019) · Molecular Immunology · doi:10.1016/j.molimm.2019.01.018 · Cited by 20
Emerging Roles for RIPK1 and RIPK3 in Pathogen-Induced Cell Death and Host Immunity
Saleh, D., & Degterev, A. (2015) · Current topics in microbiology and immunology · doi:10.1007/82_2015_449 · Cited by 19
“Mice generated with a deletion of FADD in intestinal epithelial cells (FADD) displayed diminished survival, reduced weight, and diarrhea, suggesting intestinal disease (Welz et al. 2011).”
BackgroundInfluentialThe Role of E3 Ubiquitin Ligases and Deubiquitinases in Inflammatory Bowel Disease: Friend or Foe?
Zou, M., Zeng, Q., Nie, J., Yang, J., Luo, Z.-Y., & Gan, H. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.769167 · Cited by 19
“Colonic epithelial cell necrosis and colitis were observed to occur spontaneously following IEC specific knockout of FADD in mice (135).”
BackgroundWang, M., Wang, Z., Li, Z., Qu, Y., Zhao, J., Wang, L., Zhou, X., Xu, Z., Zhang, D., Jiang, P., et al. (2024) · Phytotherapy Research · doi:10.1002/ptr.8216 · Cited by 20
“This leads to extensive epithelial erosion, PCs damage, and intestinal ulcers, culminating in spontaneous ileitis/colitis (Günther et al., 2011; Schwarzer et al., 2020; Welz et al., 2011).”
Caspases and immunity in a deadly grip
Rodrigue‐Gervais, I. G., & Saleh, M. (2012) · Trends in Immunology · doi:10.1016/j.it.2012.09.005 · Cited by 20
Modeling human gastrointestinal inflammatory diseases using microphysiological culture systems
Hartman, K. G., Bortner, J. D., Falk, G. W., Ginsberg, G. G., Jhala, N. C., Yu, J., Martı́n, M. G., Rustgi, A. K., & Lynch, J. P. (2014) · Experimental Biology and Medicine · doi:10.1177/1535370214529388 · Cited by 19
RIPK3 Suppresses the Progression of Spontaneous Intestinal Tumorigenesis
Zhao, Q., Guo, J., Cheng, X., Liao, Y., Bi, Y., Gong, Y., Zhang, X., Guo, Y., Wang, X., Yu, W., et al. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.664927 · Cited by 19
“Necroptosis is involved in intestinal inflammation in mice and human IBD patients (43, 44).”
BackgroundCellular FLICE-Inhibitory Protein Regulates Tissue Homeostasis
Nakano, H., Piao, X., Shindo, R., & Komazawa‐Sakon, S. (2015) · Current topics in microbiology and immunology · doi:10.1007/82_2015_448 · Cited by 19
“Comparing with IEC-specific NF-kB essential modulator (Nemo)-, IkB kinase (Ikk)b-, Fadd-, or Caspase-8-deficient mice (Greten et al. 2004; Gunther et al. 2011; Nenci et al. 2007; Welz et al. 2011), IEC-specific Cflip-deficient mice exhibit severe phenotypes (Piao et al.”
BackgroundThe comings and goings of cell-free DNA: Biological and clinical implications
Malki, Y., Zhou, Q. X., Jiang, P., & Lo, Y. M. D. (2025) · Med · doi:10.1016/j.medj.2025.100926 · Cited by 23
Qiu, M., Zhang, W., Dai, J., Sun, W., Lai, M., Tang, S., Xu, E., Ning, Y., & Zhan, L. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-07293-2 · Cited by 19
Metadata
- 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
- Venue
- Nature
- Published
- 2011-07-31
- Volume
- 477
- Issue
- 7364
- Pages
- 330-334
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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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