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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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Aggeletopoulou, I., Konstantakis, C., Assimakopoulos, S. F., & Triantos, C. K. (2019) · Microbial Pathogenesis · doi:10.1016/j.micpath.2019.103774 · Cited by 107
Gasdermin and MLKL necrotic cell death effectors: Signaling and diseases
Lawlor, K. E., Murphy, J. M., & Vince, J. E. (2024) · Immunity · doi:10.1016/j.immuni.2024.02.011 · Cited by 108
The Role of Necroptosis in ROS-Mediated Cancer Therapies and Its Promising Applications
Hsu, S., Chang, W., Lin, I., Chen, Y., Padalwar, N. B., Cheng, K., Teng, Y., Wang, C., & Chiu, C. (2020) · Cancers · doi:10.3390/cancers12082185 · Cited by 102
“For instance, necroptotic cell death can trigger an inflammatory response [17].”
BackgroundDziedzic, S. A., Su, Z., Barrett, V. J., Najafov, A., Mookhtiar, A. K., Amin, P. P., Pan, H., Sun, L., Zhu, H., Ma, A. I., et al. (2017) · Nature Cell Biology · doi:10.1038/s41556-017-0003-1 · Cited by 100
Liu, W., Chen, B., Wang, Y., Meng, C., Huang, H., Huang, X., Qin, J., Mulay, S. R., Anders, H., Qiu, A., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1716959115 · Cited by 99
“Necroptosis has also been shown to contribute to the pathogenesis of ischemic injury in the brain, heart, and kidney (5, 6, 8, 32, 33), atherosclerosis (34), pancreatitis (14), inflammatory bowel diseases (35), and viral infection (36).”
BackgroundLi, X., Zhang, M., Huang, X., Liang, W. P., Li, G., Lu, X., Li, Y., Pan, H., Shi, L., Zhu, H., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19935-y · Cited by 99
Xu, D., Ma, Y., Peng, C., Gan, Y., Wang, Y., Chen, Z., Han, X., & Chen, Y. (2023) · Environment International · doi:10.1016/j.envint.2023.107968 · Cited by 105
TRAF2 is a biologically important necroptosis suppressor
Petersen, S. L., Chen, T. T., Lawrence, D. A., Marsters, S. A., Gonzalvez, F., & Ashkenazi, A. (2015) · Cell Death & Differentiation · doi:10.1038/cdd.2015.35 · Cited by 99
Yang, M., Lv, Y., Tian, X., Lou, J., An, R., Zhang, Q. Y., Li, M., Xu, L., & Dong, Z. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00583 · Cited by 99
“Thus, TUNEL and cleaved caspase-3 staining were commonly used to determine necroptotic cell death (Gunther et al., 2011; Welz et al., 2011).”
BackgroundMethodNecroptosis-independent signaling by the RIP kinases in inflammation
Moriwaki, K., & Chan, F. K.-M. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2203-4 · Cited by 99
The oncogenic microRNA miR-21 promotes regulated necrosis in mice
Ma, X., Conklin, D. J., Li, F., Dai, Z., Xiang, H., Li, Y., Xu-Monette, Z. Y., Young, K. H., Xiong, W., Wysoczynski, M., et al. (2015) · Nature Communications · doi:10.1038/ncomms8151 · Cited by 99
Zhang, X., Fan, C., Zhang, H., Zhao, Q., Liu, Y., Xu, C., Xie, Q., Wu, X., Yu, X., Zhang, J., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.06.103 · Cited by 93
“Previous studies have reported that the mice with specific deficiency of Fadd or Caspase-8 in epithelial cells resulted in terminal ileitis or chronic intestinal inflammation, which was prevented by the co-deletion of Ripk3 (Welz et al., 2011).”
Philip, N. H., DeLaney, A. A., Peterson, L. W., Santos-Marrero, M., Grier, J. T., Sun, Y., Wynosky-Dolfi, M. A., Zwack, E. E., Hu, B., Olsen, T. M., et al. (2016) · PLoS Pathogens · doi:10.1371/journal.ppat.1005910 · Cited by 89
Qu, C. F., Yuan, Z., Yu, X., Huang, Y., Yang, G., Chen, J., Lai, X., Su, Z., Zeng, H., Xie, Y., et al. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.04.017 · Cited by 93
Necroptosis pathways in tumorigenesis
Zhang, T., Wang, Y., Inuzuka, H., & Wei, W. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.07.007 · Cited by 100
Martens, S., Jeong, M., Tonnus, W., Feldmann, F., Hofmans, S., Goossens, V., Takahashi, N., Bräsen, J. H., Lee, E., der Veken, P. V., et al. (2017) · Cell Death and Disease · doi:10.1038/cddis.2017.298 · Cited by 95
RIPK3 signaling and its role in regulated cell death and diseases
Zhou, Y., Xiang, Y., Liu, S., Li, C., Dong, J., Kong, X., Ji, X., Cheng, X., & Zhang, L. (2024) · Cell Death Discovery · doi:10.1038/s41420-024-01957-w · Cited by 97
“Welz et al. showed that RIPK3 had a protective effect on in fl ammation and cell death in Fas-associated protein with a novel death domain (FADD) de fi ciency-induced spontaneous colitis and ileitis models, indicating that RIPK3-mediated necrosis can lead to intestinal in fl ammation [106].”
Khan, N. R., Lawlor, K. E., Murphy, J. M., & Vince, J. E. (2013) · Current Opinion in Immunology · doi:10.1016/j.coi.2013.10.017 · Cited by 93
Necroptosis in tumorigenesis, activation of anti-tumor immunity, and cancer therapy
Meng, M.-B., Wang, H.-H., Cui, Y.-L., Wu, Z.-Q., Shi, Y., Zaorsky, N. G., Deng, L., Yuan, Z., Lü, Y., & Wang, P. (2016) · Oncotarget · doi:10.18632/oncotarget.10548 · Cited by 91
“Numerous studies have suggested that expression of RIPK3 and MLKL correlates with sensitivity to necroptosis [24, 36, 60-64], however, a potential drawback of these studies is that RIPK3 and MLKL expression were compared between healthy and inflamed tissues.”
BackgroundLiu, J., Yue, T., Luo, Z., Cao, J., Yan, Z., Jin, L., Wan, T., Shuai, C., Wang, Z., Zhou, Y., et al. (2020) · Disease Models & Mechanisms · doi:10.1242/dmm.043620 · Cited by 90
Emerging Pathological Engagement of Ferroptosis in Gut Diseases
Gao, W., Zhang, T., & Wu, H. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/4246255 · Cited by 88
Zhu, H., Wang, H., Wang, S.-H., Tu, Z., Zhang, L., Wang, X., Hou, Y., Wang, C., Chen, J., & Liu, Y. (2018) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201700814 · Cited by 85
“Several studies have demonstrated that necroptosis was involved in the dysfunction of intestinal epithelium cells [5, 44].”
RIP Kinases in Liver Cell Death, Inflammation and Cancer
Kondylis, V., & Pasparakis, M. (2018) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2018.10.007 · Cited by 85
Self-citationRegulation and Function of the Caspase-1 in an Inflammatory Microenvironment
Lee, D.-J., Du, F., Chen, S., Nakasaki, M., Rana, I., Shih, V. F.-S., Hoffmann, A., & Jamora, C. (2015) · Journal of Investigative Dermatology · doi:10.1038/jid.2015.119 · Cited by 82
“Of particular relevance are reports that deletion of RIP3 rescues the caspase-8 knockout phenotype, including cutaneous inflammation (Gunther et al., 2011; Kaiser et al., 2011; Welz et al., 2011).”
BackgroundCritical function of the necroptosis adaptor RIPK3 in protecting from intestinal tumorigenesis
Bozec, D., Iuga, A. C., Roda, G., Dahan, S., & Yeretssian, G. (2016) · Oncotarget · doi:10.18632/oncotarget.10135 · Cited by 85
“In fact, loss of caspase-8 or FADD specifically in the intestinal epithelium sensitizes IECs to necroptosis and chronic inflammatory disease that is rescued by concomitant deletion of RIPK3 [22, 23].”
BackgroundThe pathogenesis and potential therapeutic targets in sepsis
Zhang, W., Jiang, H., Wu, G., Huang, P., Wang, H., An, H., Liu, S., & Zhang, W. (2023) · MedComm · doi:10.1002/mco2.418 · Cited by 85
Wu, T. T., Peters, A. A., Tan, P. T., Roberts‐Thomson, S. J., & Monteith, G. R. (2014) · Cell Calcium · doi:10.1016/j.ceca.2014.04.006 · Cited by 80
“RNA was reverse transcribed using the Omniscript RT kit (Qiagen) and real-time RT-PCR was performed using TaqMan Universal PCR Master Mix or Taqman Fast Universal Master Mix and TaqMan gene expression assays; TRPV1 (Hs00218912_m1), cFos (Hs00170630_m1), RIP3 (Hs00819388_m1) and 18S rRNA (4319413E).”
BackgroundInfluentialRIPK3-Mediated Necroptosis Regulates Cardiac Allograft Rejection
Pavlosky, A., Lau, A., Su, Y., Lian, D., Huang, X., Yin, Z., Haig, A. R., Jevnikar, A. M., & Zhang, Z.-X. (2014) · American Journal of Transplantation · doi:10.1111/ajt.12779 · Cited by 82
c-FLIP Maintains Tissue Homeostasis by Preventing Apoptosis and Programmed Necrosis
Piao, X., Komazawa‐Sakon, S., Nishina, T., Koike, M., Piao, J., Ehlken, H., Kurihara, H., Hara, M., van Rooijen, N., Schütz, G., et al. (2012) · Science Signaling · doi:10.1126/scisignal.2003558 · Cited by 78
Necroptosis in Intestinal Inflammation and Cancer: New Concepts and Therapeutic Perspectives
Negroni, A., Colantoni, E., Cucchiara, S., & Stronati, L. (2020) · Biomolecules · doi:10.3390/biom10101431 · Cited by 81
“The first demonstration of the involvement of necroptosis in the pathogenesis of IBD derives from evidence showing that the genetic ablation of either caspsae-8 or Fadd in IECs is sufficient to induce necroptosis and spontaneous ileitis and/or colitis [62,63].”
BackgroundMelatonin attenuates carbon tetrachloride–induced liver fibrosis via inhibition of necroptosis
Choi, H., Kang, J., & Lee, S. (2015) · Translational research · doi:10.1016/j.trsl.2015.04.002 · Cited by 79
Masanetz, R. K., Winkler, J., Winner, B., Günther, C., & Süß, P. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231911111 · Cited by 80
“In the last decade, novel and more sophisticated mouse models were generated by specifically deleting proteins in IECs, such as Casp8∆IEC [26], Setdb1∆IEC [27], and Fadd∆IEC [28].”
BackgroundGiacomin, P., Moy, R. H., Noti, M., Osborne, L. C., Siracusa, M. C., Alenghat, T., Liu, B., McCorkell, K. A., Troy, A. E., Rak, G. D., et al. (2015) · The Journal of Experimental Medicine · doi:10.1084/jem.20141831 · Cited by 76
“…(IBD; Pasparakis, 2008; Marchiando et al., 2010; Maloy and Powrie, 2011), and recent studies have highlighted a critical role for innate lymphoid cells (ILCs) in regulating immunity, inflammation, and tissue repair at barrier surfaces such as the intestine (Spits and Cupedo, 2012; Walker et al.,”
BackgroundTrue Grit: Programmed Necrosis in Antiviral Host Defense, Inflammation, and Immunogenicity
Mocarski, E. S., Kaiser, W. J., Livingston‐Rosanoff, D., Upton, J. W., & Daley‐Bauer, L. P. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1302426 · Cited by 75
Cancer and necroptosis: friend or foe?
Philipp, S., Sosna, J., & Adam, D. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2193-2 · Cited by 77
“In another mouse model with genetic deficiency of FADD, the animals displayed elevated levels of necrotic intestinal epithelial cells and also developed spontaneous colitis and ileitis [89].”
Background
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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