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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Concurrent deletion of Ripk3 averts perturbations of cutaneous and intestinal homeostasis imposed by tissue-specific ablation of Fadd or Casp8.
“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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“Deficiency of caspase-8 or FADD in intestinal or skin epithelium spontaneously caused massive inflammation, which was rescued by additional deletion of RIP3 (Kovalenko et al. 2009; Bonnet et al. 2011; Gunther et al. 2011; Welz et al. 2011).”
BackgroundSignaling pathways and intervention therapies in sepsis
Zhang, Y., & Ning, B. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00816-9 · Cited by 360 · see citing works
“Though mechanisms determining apoptosis, necroptosis, or cell survival remains unclear, genetic studies revealed that FADD or caspase-8 deficiency could sensitize cells to undergo RIPK3mediated necroptosis, thus triggering embryonic lethality and inflammation.(99,100) Similarly, sufficient levels of catalytically acti…”
BackgroundProgrammed Necrosis in the Cross Talk of Cell Death and Inflammation
Chan, F. K.-M., Luz, N. F., & Moriwaki, K. (2014) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032414-112248 · Cited by 350 · see citing works
Survival Function of the FADD-CASPASE-8-cFLIPL Complex
Dillon, C. P., Oberst, A., Weinlich, R., Janke, L. J., Kang, T.-B., Ben-Moshe, T., Mak, T. W., Wallach, D., & Green, D. R. (2012) · Cell Reports · doi:10.1016/j.celrep.2012.03.010 · Cited by 331 · see citing works
“5 lethality, nor did conditional deletion of FADD in the intestine or skin (Bonnet et al., 2011; Welz et al., 2011).”
BackgroundThe therapeutic potential of targeting regulated non-apoptotic cell death
Hadian, K., & Stockwell, B. R. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00749-8 · Cited by 335 · see citing works
Cell death pathways: intricate connections and disease implications
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“Interestingly, Fadd IEC-KO ileitis was milder in Ripk3 IEC-KO or in RIP1 kinase-dead knock-in mice (Schwarzer et al , 2020) and completely inhibited by whole body RIP3 ablation (Welz et al , 2011).”
Moquin, D. M., McQuade, T., & Chan, F. K.-M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0076841 · Cited by 320 · see citing works
“necrosis-induced inflammation in different tissues [12,13].”
BackgroundRIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis
Takahashi, N., Vereecke, L., Bertrand, M. J. M., Duprez, L., Berger, S. B., Divert, T., Gonçalves, A., Sze, M., Gilbert, B., Kourula, S., et al. (2014) · Nature · doi:10.1038/nature13706 · Cited by 318 · see citing works
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“An important role of RIP3-mediated necroptosis has been demonstrated during viral infection of the liver and in tissue damage due to inflammatory bowel disease.(13) In the heart, inhibition of RIP1 by the small molecule necrostatin-1 leads to a reduction of infarct size, implying functional importance of necroptosis a…”
BackgroundRegulation of alveolar macrophage death in acute lung inflammation
Fan, E., & Fan, J. (2018) · Respiratory Research · doi:10.1186/s12931-018-0756-5 · Cited by 315 · see citing works
Gut stem cell necroptosis by genome instability triggers bowel inflammation
Wang, R., Li, H., Wu, J., Cai, Z., Li, B., Ni, H., Qiu, X., Chen, H., Liu, W., Yang, Z., et al. (2020) · Nature · doi:10.1038/s41586-020-2127-x · Cited by 310 · see citing works
Distinct roles of RIP1–RIP3 hetero- and RIP3–RIP3 homo-interaction in mediating necroptosis
Wu, X.-N., Yang, Z.-H., Wang, X.-K., Zhang, Y., Wan, H., Song, Y., Chen, X., Shao, J., & Han, J. (2014) · Cell Death & Differentiation · doi:10.1038/cdd.2014.77 · Cited by 299 · see citing works
A positive feedback loop between RIP3 and JNK controls non‐alcoholic steatohepatitis
Gautheron, J., Vucur, M., Reisinger, F., Cardenas, D. V., Roderburg, C., Koppe, C., Kreggenwinkel, K., Schneider, A. T., Bartneck, M., Neumann, U. P., et al. (2014) · EMBO Molecular Medicine · doi:10.15252/emmm.201403856 · Cited by 314 · see citing works
“Necroptosis plays a role in the regulation of chronic inflammation in the pancreas, gut, and skin (He et al , 2009; Bonnet et al , 2011; Welz et al , 2011).”
Viral infection and the evolution of caspase 8-regulated apoptotic and necrotic death pathways
Mocarski, E. S., Upton, J. W., & Kaiser, W. J. (2011) · Nature reviews. Immunology · doi:10.1038/nri3131 · Cited by 300 · see citing works
Programmed cell death and its role in inflammation
Yang, Y., Jiang, G., Zhang, P., & Fan, J. (2015) · Military Medical Research · doi:10.1186/s40779-015-0039-0 · Cited by 291 · see citing works
“This effect has been observed in a study using mice with deletion of FADD [38] or Casp8 [39] in intestinal epithelial cells (IECs) in which RIP3-dependent cell death caused intestinal inflammation.”
BackgroundInfluentialMihaly, S. R., Ninomiya‐Tsuji, J., & Morioka, S. (2014) · Cell Death and Differentiation · doi:10.1038/cdd.2014.123 · Cited by 294 · see citing works
“Similarly, epidermal- and intestinal epithelium-specific deletion of Fadd, which abrogates caspase-8 activation, causes inflammatory skin disease and IBD-like ileitis.(94,95) Although either Tak1 or Fadd/caspase-8 deletion causes cell death, the types of cell death are different.”
BackgroundOnizawa, M., Oshima, S., Schulze-Topphoff, U., Oses-Prieto, J. A., Lu, T., Tavares, R., Prodhomme, T., Duong, B., Whang, M. I., Advincula, R., et al. (2015) · Nature Immunology · doi:10.1038/ni.3172 · Cited by 284 · see citing works
Cell death and inflammation during obesity: “Know my methods, WAT(son)”
Hildebrandt, X., Ibrahim, M. A., & Peltzer, N. (2022) · Cell Death and Differentiation · doi:10.1038/s41418-022-01062-4 · Cited by 283 · see citing works
“It is puzzling that FADD deficiency does not unleash necroptosis in adipocytes as it does in many other cells [40, 69, 70].”
ROS in gastrointestinal inflammation: Rescue Or Sabotage?
Aviello, G., & Knaus, U. G. (2016) · British Journal of Pharmacology · doi:10.1111/bph.13428 · Cited by 282 · see citing works
“Transgenic mice with conditional deletion of caspase-8 (Casp8ΔIEC) (Gunther et al., 2011) or FADD (FADDIEC-KO) (Welz et al., 2011) in the intestinal epithelium spontaneously developed inflammatory lesions in the terminal ileum, lacked Paneth cells and exhibited severe colitis in a dextran sodium sulphate (DSS) colitis…”
BackgroundSchwarzer, R., Jiao, H., Wachsmuth, L., Tresch, A., & Pasparakis, M. (2020) · Immunity · doi:10.1016/j.immuni.2020.04.002 · Cited by 277 · see citing works
Self-citationYu, L. C. (2012) · World Journal of Gastrointestinal Pathophysiology · doi:10.4291/wjgp.v3.i1.27 · Cited by 270 · see citing works
XIAP Restricts TNF- and RIP3-Dependent Cell Death and Inflammasome Activation
Yabal, M., Müller, N., Adler, H., Knies, N., Groß, C. J., Damgaard, R. B., Kanegane, H., Ringelhan, M., Kaufmann, T., Heikenwälder, M., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.05.008 · Cited by 255 · see citing works
“Necroptosis-inhibiting proteins are therefore critical regulators of tissue homeostasis (Günther et al., 2011; Kang et al., 2013; Welz et al., 2011).”
A Role of RIP3-Mediated Macrophage Necrosis in Atherosclerosis Development
Lin, J., Li, H., Yang, M. H., Ren, J., Huang, Z., Han, F., Huang, J., Ma, J., Zhang, D., Zhang, Z., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2012.12.012 · Cited by 266 · see citing works
Wang, J., Zhang, X.-J., Li, Q., Wang, K., Wang, Y., Jiao, J.-Q., Feng, C., Sun, T., Zhou, L., Gong, Y., et al. (2015) · Circulation Research · doi:10.1161/circresaha.117.305781 · Cited by 265 · see citing works
Chen, W., Zhou, Z., Li, L., Zhong, C., Zheng, X., Wu, X., Zhang, Y., Ma, H., Huang, D., Li, W., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.435545 · Cited by 265 · see citing works
“In addition to host defense, necroptosis is also involved in chronic inflammation and tissue injury (6), such as chronic intestinal inflammation (7, 8), liver injury (9), skin inflammation (10), retinal detachment (11, 12), hemolysis (13), and atherosclerosis (14).”
BackgroundThe Necroptosis Adaptor RIPK3 Promotes Injury-Induced Cytokine Expression and Tissue Repair
Moriwaki, K., Balaji, S., McQuade, T. J., Malhotra, N., Kang, J., & Chan, F. K.-M. (2014) · Immunity · doi:10.1016/j.immuni.2014.09.016 · Cited by 251 · see citing works
“For example, tissue-specific deletion of FADD or caspase 8 in keratinocytes or intestinal epithelium led to spontaneous inflammation that is rescued by inactivation of RIPK3 (Bonnet et al., 2011; Günther et al., 2011; Welz et al., 2011).”
InfluentialThe Paneth Cell: The Curator and Defender of the Immature Small Intestine
Lueschow, S. R., & McElroy, S. J. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00587 · Cited by 255 · see citing works
“This is now thought to be due to the high expression of RIP3, a keymodulator of necroptosis, in Paneth cells of humans and mice (84, 95, 96).”
BackgroundMethodPhotoreceptor cell death and rescue in retinal detachment and degenerations
Murakami, Y., Notomi, S., Hisatomi, T., Nakazawa, T., Ishibashi, T., Miller, J. W., & Vavvas, D. G. (2013) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2013.08.001 · Cited by 248 · see citing works
“It has been shown that Rip3 deficiency ameliorates inflammation as well as necrosis in models of sepsis, colitis, and RD (Duprez et al., 2011; Welz et al., 2011; Trichonas et al., 2010).”
Determination of apoptotic and necrotic cell death in vitro and in vivo
Berghe, T. V., Grootjans, S., Goossens, V., Dondelinger, Y., Krysko, D. V., Takahashi, N., & Vandenabeele, P. (2013) · Methods · doi:10.1016/j.ymeth.2013.02.011 · Cited by 250 · see citing works
Wenzel, J., Lampe, J., Müller‐Fielitz, H., Schuster, R., Zille, M., Müller, K., Krohn, M., Körbelin, J., Zhang, L., Özorhan, Ü., et al. (2021) · Nature Neuroscience · doi:10.1038/s41593-021-00926-1 · Cited by 252 · see citing works
Self-citationGlutathione peroxidase 4 prevents necroptosis in mouse erythroid precursors
Canli, Ö., Alankuş, Y. B., Grootjans, S., Vegi, N., Hültner, L., Hoppe, P. S., Schroeder, T., Vandenabeele, P., Bornkamm, G. W., & Greten, F. R. (2016) · Blood · doi:10.1182/blood-2015-06-654194 · Cited by 247 · see citing works
RIP kinases as modulators of inflammation and immunity
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The Impact of Autophagy on Cell Death Modalities
Ryter, S. W., Mizumura, K., & Choi, A. M. K. (2014) · International Journal of Cell Biology · doi:10.1155/2014/502676 · Cited by 248 · see citing works
“Binding of these Bcl-2 family proteins to Beclin 1 inhibits autophagy by preventing the association of Beclin 1 with the class III PI3K complex [57, 60].”
BackgroundDeath Receptor-Ligand Systems in Cancer, Cell Death, and InflammationPreprint
Walczak, H. (2013) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a008698 · Cited by 243 · see citing works
“Interestingly, recent studies have shown that inflammation in mice deficient for caspase-8 or FADD in either skin or gut (Kovalenko et al. 2009), does not occur when RIP3 is absent (Welz et al. 2011; Gunther et al. 2012).”
BackgroundLi, J., Feng, J.-M., Wang, Y., Li, X.-H., Chen, X.-X., Su, Y., Shen, Y.-Y., Chen, Y., Xiong, B., Yang, C.-H., et al. (2014) · Cell Death and Disease · doi:10.1038/cddis.2014.241 · Cited by 233 · see citing works
The Spectrum of Achalasia: Lessons From Studies of Pathophysiology and High-Resolution Manometry
Kahrilas, P. J., & Boeckxstaens, G. E. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.08.038 · Cited by 234 · see citing works
An Inflammatory Perspective on Necroptosis
Kearney, C. J., & Martin, S. J. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.02.024 · Cited by 227 · see citing works
Innate immune signalling at the intestinal epithelium in homeostasis and disease
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Tumour Necrosis Factor Alpha in Intestinal Homeostasis and Gut Related Diseases
Ruder, B., Atreya, R., & Becker, C. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20081887 · Cited by 228 · see citing works
“However, being in line with the study mentioned above, TNFα was not the main driver of inflammation and epithelial cell death in the small intestine [114], suggesting that cell death regulation in the small and large intestine differ.”
ResultTNF and ubiquitin at the crossroads of gene activation, cell death, inflammation, and cancer
Walczak, H. (2011) · Immunological Reviews · doi:10.1111/j.1600-065x.2011.01066.x · Cited by 222 · see citing works
“However, at least for programmed necrosis, this does not always seem to be the case (134).”
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Self-citationNajafov, A., Chen, H., & Yuan, J. (2017) · Trends in cancer · doi:10.1016/j.trecan.2017.03.002 · Cited by 225 · see citing works
“A tight connection between necroptosis and intestinal inflammation has been established in various mouse models [48,49].”
Crosstalk between Long Noncoding RNAs and MicroRNAs in Health and Disease
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Pierdomenico, M., Negroni, A., Stronati, L., Vitali, R., Prete, E., Bertin, J., Gough, P. J., Aloi, M., & Cucchiara, S. (2013) · The American Journal of Gastroenterology · doi:10.1038/ajg.2013.403 · Cited by 217 · see citing works
The ‘complexities’ of life and death: Death receptor signalling platforms
Dickens, L. S., Powley, I. R., Hughes, M. A., & MacFarlane, M. (2012) · Experimental Cell Research · doi:10.1016/j.yexcr.2012.04.005 · Cited by 208 · see citing works
Tumour necrosis factor and cancer
Waters, J. P., Pober, J. S., & Bradley, J. R. (2013) · The Journal of Pathology · doi:10.1002/path.4188 · Cited by 209 · see citing works
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Mitochondria released by cells undergoing TNF-α-induced necroptosis act as danger signals
Maeda, A., & Fadeel, B. (2014) · Cell Death & Disease · doi:10.1038/cddis.2014.277 · Cited by 201 · see citing works
RIPK3-Mediated Necroptosis Promotes Donor Kidney Inflammatory Injury and Reduces Allograft Survival
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Targeting Cell Death: Pyroptosis, Ferroptosis, Apoptosis and Necroptosis in Osteoarthritis
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“, 2013), inflammatory bowel disease (Welz et al., 2011), and several other common clinical disorders (Linkermann, 2014).”
BackgroundRemijsen, Q., Goossens, V., Grootjans, S., den Haute, C. V., Vanlangenakker, N., Dondelinger, Y., Roelandt, R., Bruggeman, I., Gonçalves, A. C., Bertrand, M. J. M., et al. (2014) · Cell Death and Disease · doi:10.1038/cddis.2013.531 · Cited by 203 · see citing works
Control of Life-or-Death Decisions by RIP1 Kinase
Christofferson, D. E., Li, Y., & Yuan, J. (2013) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021113-170259 · Cited by 200 · see citing works
Gut epithelial TSC1/mTOR controls RIPK3-dependent necroptosis in intestinal inflammation and cancer
Xie, Y., Zhao, Y., Shi, L., Li, W., Chen, K., Li, M., Chen, X., Zhang, H., Li, T., Matsuzawa, Y., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci133264 · Cited by 198 · see citing works
“Although RIPK3 overexpression exhibited in Tsc1 IECs resembles what has been shown in Casp8 and Fadd IECs (19, 28), unlike Casp8 and Fadd IECs, Tsc1 IECs did not upregulate the expression of Ripk3 mRNAs (Supplementary Figure 6A).”
BackgroundResultInfluential
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › 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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