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

The DOI matches its Crossref record; 36 of the 36 references it cites were found in a registry or an index.

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

Open access

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

Open this paper in CoChat — free account

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.

Integrity signals

Registry

Crossref · 10.1038/nature10273

Cites

36 of 36 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Unravelling the pathogenesis of inflammatory bowel disease
Xavier, R. J., & Podolsky, D. K. (2007) · Nature · doi:10.1038/nature06005 · Cited by 4,364
Intestinal mucosal barrier function in health and disease
Turner, J. R. (2009) · Nature reviews. Immunology · doi:10.1038/nri2653 · Cited by 3,952
Phosphorylation-Driven Assembly of the RIP1-RIP3 Complex Regulates Programmed Necrosis and Virus-Induced Inflammation
Cho, Y., Challa, S., Moquin, D., Genga, R., Ray, T. D., Guildford, M., & Chan, F. K.-M. (2009) · Cell · doi:10.1016/j.cell.2009.05.037 · Cited by 2,435
Molecular mechanisms of necroptosis: an ordered cellular explosion
Vandenabeele, P., Galluzzi, L., Vanden Berghe, T., & Kroemer, G. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2970 · Cited by 2,382
Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function.
Adachi, O., Kawai, T., Takeda, K., Matsumoto, M., Tsutsui, H., Sakagami, M., Nakanishi, K., & Akira, S. (1998) · Immunity · doi:10.1016/s1074-7613(00)80596-8 · Cited by 2,358
Receptor Interacting Protein Kinase-3 Determines Cellular Necrotic Response to TNF-α
He, S., Wang, L., Miao, L., Wang, T., Du, F., Zhao, L., & Wang, X. (2009) · Cell · doi:10.1016/j.cell.2009.05.021 · Cited by 2,214
Fas triggers an alternative, caspase-8–independent cell death pathway using the kinase RIP as effector molecule
Holler, N., Zaru, R., Micheau, O., Thome, M., Attinger, A., Valitutti, S., Bodmer, J.-L., Schneider, P., Seed, B., & Tschopp, J. (2000) · Nature Immunology · doi:10.1038/82732 · Cited by 1,987
RIP3, an Energy Metabolism Regulator That Switches TNF-Induced Cell Death from Apoptosis to Necrosis
Zhang, D.-W., Shao, J., Lin, J., Zhang, N., Lu, B.-J., Lin, S.-C., Dong, M.-Q., & Han, J. (2009) · Science · doi:10.1126/science.1172308 · Cited by 1,931
Inflammatory bowel disease
Kaser, A., Zeissig, S., & Blumberg, R. S. (2010) · Annual Review of Immunology · doi:10.1146/annurev-immunol-030409-101225 · Cited by 1,806
A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells
Cadwell, K., Liu, J. Y., Brown, S. L., Miyoshi, H., Loh, J., Lennerz, J. K., Kishi, C., Kc, W., Carrero, J. A., Hunt, S., et al. (2008) · Nature · doi:10.1038/nature07416 · Cited by 1,542

Flagged first, then by citations

Show all 36 references

Sorted by citations

Items 201–300 of 601

A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis
Takezaki, A., Tsukumo, S., Setoguchi, Y., Ledford, J. G., Goto, H., Hosomichi, K., Uehara, H., Nishioka, Y., & Yasutomo, K. (2019) · The Journal of Experimental Medicine · doi:10.1084/jem.20182351 · Cited by 80
“There are several studies that implicate necroptosis in tissue inflammation in animal models (Bonnet et al., 2011; Welz et al., 2011; Wu et al., 2013).”
The effects of moderate exercise on chronic stress-induced intestinal barrier dysfunction and antimicrobial defense
Luo, B., Xiang, D., Nieman, D. C., & Chen, P. (2014) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2013.11.013 · Cited by 74
New components of the necroptotic pathway
Zhou, Z., Han, V. K. M., & Han, J. (2012) · Protein & Cell · doi:10.1007/s13238-012-2083-9 · Cited by 75
The Epithelial Danger Signal IL-1α Is a Potent Activator of Fibroblasts and Reactivator of Intestinal Inflammation
Scarpa, M., Kessler, S. P., Sadler, T. M., West, G. A., Homer, C. R., McDonald, C., de la Motte, C., Fiocchi, C., & Stylianou, E. (2015) · American Journal Of Pathology · doi:10.1016/j.ajpath.2015.02.018 · Cited by 78
Ginkgolides and bilobalide protect BV2 microglia cells against OGD/reoxygenation injury by inhibiting TLR2/4 signaling pathways
Zhou, J., Gu, S.-S., Mei, W. H., Zhou, J., Wang, Z. Z., & Xiao, W. (2016) · Cell Stress and Chaperones · doi:10.1007/s12192-016-0728-y · Cited by 75
“RIP3 is a key molecular Bswitch^ in tumor necrosis factor-induced apoptosis, necrosis, and necroptosis (Welz et al. 2011; Sosna et al. 2014), and we examined RIP3 expression in OGD/R-induced BV2 microglia cells and the role of ginkgolides and BB.”
Background
Regulation of RIP3 by the transcription factor Sp1 and the epigenetic regulator UHRF1 modulates cancer cell necroptosis
Yang, C., Li, J., Yu, L., Zhang, Z., Xu, F., Jiang, L., Zhou, X., & He, S. (2017) · Cell Death and Disease · doi:10.1038/cddis.2017.483 · Cited by 76
Inhibition of receptor-interacting protein 3 upregulation and nuclear translocation involved in Necrostatin-1 protection against hippocampal neuronal programmed necrosis induced by ischemia/reperfusion injury
Yin, B., Xu, Y., Wei, R., He, F., Luo, B., & Wang, J. (2015) · Brain Research · doi:10.1016/j.brainres.2015.03.024 · Cited by 74
On cell death in the intestinal epithelium and its impact on gut homeostasis
Blander, J. M. (2018) · Current Opinion in Gastroenterology · doi:10.1097/mog.0000000000000481 · Cited by 71
ABIN3 Negatively Regulates Necroptosis-induced Intestinal Inflammation Through Recruiting A20 and Restricting the Ubiquitination of RIPK3 in Inflammatory Bowel Disease
Zhou, M., He, J., Shi, Y., Liu, X., Luo, S., Cheng, C., Ge, W., Qu, C.-Y., Du, P., & Chen, Y. (2020) · Journal of Crohn s and Colitis · doi:10.1093/ecco-jcc/jjaa131 · Cited by 73
Regulated necrosis, a proinflammatory cell death, potentially counteracts pathogenic infections
Zhang, G., Wang, J., Zhao, Z., Xin, T., Fan, X., Shen, Q., Raheem, A., Lee, C. R., Jiang, H., & Ding, J. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-05066-3 · Cited by 75
“The presence of caspase-8 in the necrosome can prevent the interaction of RIP1 and RIP3 via the direct cleavage of these two kinases [50, 62, 63].”
Background
RIP1-mediated mitochondrial dysfunction and ROS production contributed to tumor necrosis factor alpha-induced L929 cell necroptosis and autophagy
Ye, Y., Wang, H., Yu, L., Tashiro, S., Onodera, S., & Ikejima, T. (2012) · International Immunopharmacology · doi:10.1016/j.intimp.2012.08.003 · Cited by 73
“Necroptosis regulates the normal embryonic development, T-cell proliferation and chronic intestinal inflammation [4–7].”
Background
Necroptosis in cancer: An angel or a demon?
Wang, T., Jin, Y., Yang, W., Zhang, L., Jin, X., Liu, X., He, Y., & Li, X. (2017) · Tumor Biology · doi:10.1177/1010428317711539 · Cited by 72
Inhibition of Phosphoglycerate Mutase 5 Reduces Necroptosis in Rat Hearts Following Ischemia/Reperfusion Through Suppression of Dynamin-Related Protein 1
She, L., Tu, H., Zhang, Y.-Z., Tang, L.-J., Li, N., Ma, Q.-L., Liu, B., Li, Q., Luo, X., & Peng, J. (2019) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-018-06848-8 · Cited by 72
The natural compound celastrol inhibits necroptosis and alleviates ulcerative colitis in mice
Jia, Z., Xu, C., Shen, J., Xia, T., Yang, J., & He, Y. (2015) · International Immunopharmacology · doi:10.1016/j.intimp.2015.09.029 · Cited by 71
The effects of the microbiota on the host immune system
Karczewski, J., Poniedziałek, B., Adamski, Z., & Rzymski, P. (2014) · Autoimmunity · doi:10.3109/08916934.2014.938322 · Cited by 73
“This in turn, leads to the further destruction of the epithelium resulting in chronic intestinal inflammation [59].”
Background
Akt Regulates TNFα Synthesis Downstream of RIP1 Kinase Activation during Necroptosis
McNamara, C. R., Ahuja, R., Osafo-Addo, A. D., Barrows, D., Kettenbach, A. N., Skidan, I. N., Teng, X., Cuny, G. D., Gerber, S. A., & Degterev, A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0056576 · Cited by 69
“Two recent papers showed that the loss of control over RIP1/RIP3 kinase activities by FADD and caspase-8 in epithelial cells unleashes a feed forward cycle of necroptosis and TNFa production, resulting in the development of intestinal inflammation in mice and, possibly, in patients with Crohn’s disease [4,5].”
Background
Inhibitor of Apoptosis Protein-1 Regulates Tumor Necrosis Factor–Mediated Destruction of Intestinal Epithelial Cells
Grabinger, T., Bode, K. J., Demgenski, J., Seitz, C., Delgado, M. E., Kostadinova, F. I., Reinhold, C., Etemadi, N., Wilhelm, S., Schweinlin, M., et al. (2016) · Gastroenterology · doi:10.1053/j.gastro.2016.11.019 · Cited by 66
Inflammatory signals that regulate intestinal epithelial renewal, differentiation, migration and cell death: Implications for necrotizing enterocolitis
Kandasamy, J., Huda, S. A., Ambalavanan, N., & Jilling, T. (2014) · Pathophysiology · doi:10.1016/j.pathophys.2014.01.001 · Cited by 70
EPA and DHA attenuate deoxynivalenol‐induced intestinal porcine epithelial cell injury and protect barrier function integrity by inhibiting necroptosis signaling pathway
Xiao, K., Liu, C., Qin, Q., Zhang, Y., Wang, X., Zhang, J., Odle, J., Lin, X., Hu, C. A., & Liu, Y. (2019) · The FASEB Journal · doi:10.1096/fj.201902298r · Cited by 68
Chlorogenic Acid Ameliorates Post‐Infectious Irritable Bowel Syndrome by Regulating Extracellular Vesicles of Gut Microbes
Zheng, C., Zhong, Y., Zhang, W., Wang, Z., Xiao, H., Zhang, W., Xie, J., Peng, X., Luo, J. F., & Xu, W. (2023) · Advanced Science · doi:10.1002/advs.202302798 · Cited by 69
Cellular FLICE-Like Inhibitory Protein Secures Intestinal Epithelial Cell Survival and Immune Homeostasis by Regulating Caspase-8
Wittkopf, N., Günther, C., Martini, E., He, G.-W., Amann, K., He, Y.-W., Schuchmann, M., Neurath, M. F., & Becker, C. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.08.059 · Cited by 68
The mammalian intestinal epithelium as integral player in the establishment and maintenance of host–microbial homeostasis
Duerr, C. U., & Hornef, M. W. (2011) · Seminars in Immunology · doi:10.1016/j.smim.2011.11.002 · Cited by 67
“[127] Welz PS, Wullaert A, Vlantis K, Kondylis V, Fernandez-Majada V, Ermolaeva M, et al.”
Background
Uncovering Pathogenic Mechanisms of Inflammatory Bowel Disease Using Mouse Models of Crohn’s Disease–Like Ileitis: What is the Right Model?
Cominelli, F., Arseneau, K. O., Rodriguez‐Palacios, A., & Pizarro, T. T. (2017) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2017.02.010 · Cited by 68
RIPK 3‐driven cell death during virus infections
Upton, J. W., Shubina, M., & Balachandran, S. (2017) · Immunological Reviews · doi:10.1111/imr.12539 · Cited by 71
Crosstalk Between the Intestinal Microbiota and the Innate Immune System in Intestinal Homeostasis and Inflammatory Bowel Disease
Dupaul-Chicoine, J., Dagenais, M., & Saleh, M. (2013) · Inflammatory Bowel Diseases · doi:10.1097/mib.0b013e31828dcac7 · Cited by 68
“to occur at the bottom of the crypt, more specifically in Paneth cells, and to be microbiota dependent and TNF dependent.(40,41)”
The CD95/CD95L signaling pathway: A role in carcinogenesis
Fouqué, A., Debure, L., & Legembre, P. (2014) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2014.04.007 · Cited by 72
Loss of RIP3 initiates annihilation of high-fat diet initialized nonalcoholic hepatosteatosis: A mechanism involving Toll-like receptor 4 and oxidative stress
Ge, C., Xu, M., Qin, Y., Gu, T.-T., Feng, J., Jinxiao, L., Sujun, W., Ma, Y., Deshuai, L., Qiang, L., et al. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.12.034 · Cited by 63
Necroptosis: Who Knew There were so Many Interesting Ways to Die?
Fayaz, S. M., Kumar, V. S. S., & Rajanikant, G. K. (2014) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/18715273113126660189 · Cited by 65
Necroptosis: Molecular Signalling and Translational Implications
Giampietri, C., Starace, D., Petrungaro, S., Filippini, A., & Ziparo, E. (2014) · International Journal of Cell Biology · doi:10.1155/2014/490275 · Cited by 63
“It has been demonstrated that mechanisms preventing RIP3-mediated epithelial cell death are crucial for maintaining intestinal homeostasis [67].”
Background
The Tumor Suppressor Hace1 Is a Critical Regulator of TNFR1-Mediated Cell Fate
Tortola, L., Nitsch, R., Bertrand, M. J. M., Kogler, M., Redouane, Y., Kozieradzki, I., Uribesalgo, I., Fennell, L. M., Daugaard, M., Klug, H., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.04.032 · Cited by 64
“Colonoscopies were performed as previously described (Welz et al., 2011).”
Zeb2 drives invasive and microbiota-dependent colon carcinoma
Slowicka, K., Πέττα, Ι., Blancke, G., Hoste, E., Dumas, E., Sze, M., Vikkula, H., Radaelli, E., Haigh, J. J., Jonckheere, S., et al. (2020) · Nature Cancer · doi:10.1038/s43018-020-0070-2 · Cited by 64
Self-citation
The role of RIPK3‐regulated cell death pathways and necroptosis in the pathogenesis of cardiac ischaemia‐reperfusion injury
Luo, Y., Benjanuwattra, J., Chattipakorn, S. C., & Chattipakorn, N. (2020) · Acta Physiologica · doi:10.1111/apha.13541 · Cited by 65
Necroptosis Signaling Pathways in Stroke: From Mechanisms to Therapies
Huang, J., Li, Y., Zhao, B.-L., Li, J., Zhang, N., Ye, Z., Xue-Jun, S., & Wen-wu, L. (2018) · Current Neuropharmacology · doi:10.2174/1570159x16666180416152243 · Cited by 61
“Recently, studies have implicated necroptosis in a variety of disease states, and it has a central pathophysiological relevance in some diseases including stroke [27], myocardial ischemia/reperfusion (I/R) injury [28], atherosclerosis [29], renal I/R injury [30], pancreatitis [31], inflammatory bowel disease [32] and…”
Background
Targeting necroptosis as therapeutic potential in chronic myocardial infarction
Piamsiri, C., Maneechote, C., Siri‐Angkul, N., Chattipakorn, S. C., & Chattipakorn, N. (2021) · Journal of Biomedical Science · doi:10.1186/s12929-021-00722-w · Cited by 66
Inhibition of Necroptosis Attenuates Kidney Inflammation and Interstitial Fibrosis Induced By Unilateral Ureteral Obstruction
Xiao, X., Du, C., Yan, Z., Shi, Y., Duan, H., & Ren, Y. (2017) · American Journal of Nephrology · doi:10.1159/000478746 · Cited by 60
c-Jun N-terminal kinases differentially regulate TNF- and TLRs-mediated necroptosis through their kinase-dependent and -independent activities
Cao, M., Chen, F., Xie, N., Cao, M.-Y., Chen, P., Lou, Q., Zhao, Y., He, C., Zhang, S., Song, X., et al. (2018) · Cell Death and Disease · doi:10.1038/s41419-018-1189-2 · Cited by 61
Functional Mammalian Amyloids and Amyloid-Like Proteins
Rubel, M. S., Fedotov, S. A., Grizel, A. V., Sopova, J. V., Malikova, O. A., Chernoff, Y. O., & Rubel, A. A. (2020) · Life · doi:10.3390/life10090156 · Cited by 61
Ubiquitylation in immune disorders and cancer: from molecular mechanisms to therapeutic implications
Fulda, S., Rajalingam, K., & Đikić, I. (2012) · EMBO Molecular Medicine · doi:10.1002/emmm.201100707 · Cited by 57
“Recent studies with various mouse models revealed a crucial tissue-speciﬁc role of RIP1-RIP3 in regulating necroptosis-mediated inﬂammation (Bonnet et al, 2011; Duprez et al, 2011; Gunther et al, 2011; Kaiser et al, 2011; Welz et al, 2011).”
The tumour suppressor CYLD regulates the p53 DNA damage response
Fernández‐Majada, V., Welz, P.-S., Ermolaeva, M., Schell, M. J., Adam, A. C., Dietlein, F., Komander, D., Büttner, R., Thomas, R. K., Schumacher, B., et al. (2016) · Nature Communications · doi:10.1038/ncomms12508 · Cited by 57
Self-citation
Death receptor signalling in central nervous system inflammation and demyelination
Guire, C. M., Beyaert, R., & Loo, G. (2011) · Trends in Neurosciences · doi:10.1016/j.tins.2011.09.002 · Cited by 59
Diet, Microbiome, and the Intestinal Epithelium: An Essential Triumvirate?
Guzman, J. R., Conlin, V. S., & Jobin, C. (2013) · BioMed Research International · doi:10.1155/2013/425146 · Cited by 61
“Mice with IEC-specific deletion of FADD showed reduced weight, diarrhea, and the development of spontaneous colitis, and the IECs of which were shown to have undergone necrotic cell death not apoptosis [55].”
Background
Death Receptors and Their Ligands in Inflammatory Disease and CancerPreprint
Annibaldi, A., & Walczak, H. (2020) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a036384 · Cited by 61
“Other genetic mouse models of inflammatory disease have also been shown to be driven by excessive cell death (Welz et al. 2011; Dannappel et al. 2014; Kumari et al. 2014; Vlantis et al. 2016).”
Background
Toll-like receptor 4-mediated necroptosis in the development of necrotizing enterocolitis
Liu, T., Zong, H., Chen, X., Li, S., Liu, Z., Cui, X., Jia, G., & Shi, Y. (2021) · Pediatric Research · doi:10.1038/s41390-021-01457-y · Cited by 60
Hematopoietic stem cell quiescence and function are controlled by the CYLD–TRAF2–p38MAPK pathway
Tesio, M., Tang, Y., Müdder, K., Saini, M., von Paleske, L., Macintyre, E. A., Pasparakis, M., Waisman, A., & Trumpp, A. (2015) · The Journal of Experimental Medicine · doi:10.1084/jem.20141438 · Cited by 58
“CYLD932flox/flox (control) mice, generated as previously described (Welz et al., 2011), were crossed with the Mx1-Cre transgenic mice (Kühn et al., 1995) to obtain MxCre;CYLD932flox/flox (mutant) animals.”
BackgroundMethodSelf-citation
Matrine induces RIP3-dependent necroptosis in cholangiocarcinoma cells
Xu, B., Xu, M., Tian, Y., Yu, Q., Zhao, Y., Chen, X., Mi, P., Cao, H., Zhang, B., Song, G., et al. (2017) · Cell Death Discovery · doi:10.1038/cddiscovery.2016.96 · Cited by 54
Necrostatin-1 Attenuates Cisplatin-Induced Nephrotoxicity Through Suppression of Apoptosis and Oxidative Stress and Retains Klotho Expression
Ning, Y., Shi, Y., Chen, J., Song, N., Cai, J., Fang, Y., Yu, X., Ji, J., & Ding, X. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00384 · Cited by 55
“This provides in vivo experimental evidence that necroptosis of epithelial cells mediated by RIPK3 induces intestinal inflammation (Welz et al., 2011).”
Background
Atrazine induces necroptosis by miR-181–5p targeting inflammation and glycometabolism in carp lymphocytes
Cui, Y., Yin, K., Gong, Y., Qu, Y., Liu, H., & Lin, H. (2019) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2019.09.068 · Cited by 55
Airway epithelial cell necroptosis contributes to asthma exacerbation in a mouse model of house dust mite-induced allergic inflammation
Oikonomou, N., Schuijs, M. J., Chatzigiagkos, A., Androulidaki, A., Aidinis, V., Hammad, H., Lambrecht, B. N., & Pasparakis, M. (2021) · Mucosal Immunology · doi:10.1038/s41385-021-00415-5 · Cited by 54
“We reasoned that AEC-specific FADD deficiency might cause exacerbated airway inflammation in response to HDM by sensitizing AECs to necroptosis, as was previously shown in mice lacking FADD specifically in epidermal keratinocytes or intestinal epithelial cells.(24,25) RIPK1 kinase activity is required for TNFR1- and T…”
BackgroundSelf-citation
Necroptosis, Pyroptosis, Ferroptosis in Sepsis and Treatment
Qu, M., Wang, Y., Qiu, Z., Zhu, S., Guo, K., Chen, W., Miao, C., & Zhang, H. (2022) · Shock · doi:10.1097/shk.0000000000001936 · Cited by 61
Targeting cell death signaling in colorectal cancer: Current strategies and future perspectives
Koehler, B. C. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i8.1923 · Cited by 55
Loss of Caspase-3 sensitizes colon cancer cells to genotoxic stress via RIP1-dependent necrosis
Brown, M. F., Leibowitz, B. J., Chen, D., He, K., Zou, F., Sobol, R. W., Beer–Stolz, D., Zhang, L., & Yu, J. (2015) · Cell Death and Disease · doi:10.1038/cddis.2015.104 · Cited by 55
“In mice, loss of caspase-8 leads to RIP3dependent necrosis and embryonic lethality,(10,11) or intestinal inflammation involving TNF-α production.(12,13) In HT29 colon”
Post-translational control of RIPK3 and MLKL mediated necroptotic cell death
Murphy, J. M., & Vince, J. E. (2015) · F1000Research · doi:10.12688/f1000research.7046.1 · Cited by 55
Locking mixed-lineage kinase domain-like protein in its auto-inhibited state prevents necroptosis
Rübbelke, M., Fiegen, D., Bauer, M., Binder, F. P. C., Hamilton, J. Y., King, J., Thamm, S., Nar, H., & Zeeb, M. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2017406117 · Cited by 54
“Consequently, necroptosis has been associated with several inflammatory diseases, including amyotrophic lateral sclerosis (4), chronic intestinal inflammation (5), and skin inflammation (6).”
Background
Inhibition of HtrA2 alleviated dextran sulfate sodium (DSS)-induced colitis by preventing necroptosis of intestinal epithelial cells
Zhang, C., He, A., Liu, S., He, Q., Luo, Y., He, Z., Chen, Y., Tao, A., & Yan, J. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1580-7 · Cited by 52
Manipulation of necroptosis by Porphyromonas gingivalis in periodontitis development
Ke, X., Lei, L., Li, H., Li, H., & Yan, F. (2016) · Molecular Immunology · doi:10.1016/j.molimm.2016.07.010 · Cited by 52
OTULIN inhibits RIPK1-mediated keratinocyte necroptosis to prevent skin inflammation in mice
Schünke, H., Göbel, U., Đikić, I., & Pasparakis, M. (2021) · Nature Communications · doi:10.1038/s41467-021-25945-1 · Cited by 53
Self-citation
FADD regulates NF-κB activation and promotes ubiquitination of cFLIPL to induce apoptosis
Ranjan, K., & Pathak, C. (2016) · Scientific Reports · doi:10.1038/srep22787 · Cited by 53
TNFR1-induced lethal inflammation is mediated by goblet and Paneth cell dysfunction
Hauwermeiren, F. V., Vandenbroucke, R. E., Grine, L., Lodens, S., Wonterghem, E. V., Rycke, R. M. D., Geest, N. D., Hassan, B. A., & Libert, C. (2014) · Mucosal Immunology · doi:10.1038/mi.2014.112 · Cited by 52
“A similar mechanism was proposed for the induction of IBD-like intestinal inflammation.(55,56) In both of these studies, the initial stimulus was TNF-induced damage to the IEC, whereas the second stimulus was Myd88 dependent.”
Background
Interaction of Dietary Fatty Acids with Tumour Necrosis Factor Family Cytokines during Colon Inflammation and Cancer
Hofmanová, J., Straková, N., Vaculová, A. H., Tylichová, Z., Šafaříková, B., Skender, B., & Kozubı́k, A. (2014) · Mediators of Inflammation · doi:10.1155/2014/848632 · Cited by 50
“Association of necroptosis and intestinal inflammation through specific activation of TNF-α synthesis by RIP1 and Akt kinase pathway has been documented [41].”
Background
MLKL-PITPα signaling-mediated necroptosis contributes to cisplatin-triggered cell death in lung cancer A549 cells
Jing, L., Song, F., Liu, Z., Li, J., Wu, B., Fu, Z., Jiang, J., & Chen, Z. (2017) · Cancer Letters · doi:10.1016/j.canlet.2017.10.047 · Cited by 52
RIP3 knockdown inhibits necroptosis of human intestinal epithelial cells via TLR4/MyD88/NF-κB signaling and ameliorates murine colitis
Duan, C., Xi, X., Lu, X., Wang, X., & Lu, Z. (2022) · BMC Gastroenterology · doi:10.1186/s12876-022-02208-x · Cited by 53
Wall of Resilience: How the Intestinal Epithelium Prevents Inflammatory Onslaught in the Gut
Liebing, E., Krug, S. M., Neurath, M. F., Siegmund, B., & Becker, C. (2024) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2024.101423 · Cited by 52
RIPK3 Mediates Necroptosis during Embryonic Development and Postnatal Inflammation in Fadd-Deficient Mice
Zhao, Q., Yu, X., Zhang, H., Liu, Y., Zhang, X., Wu, X., Xie, Q., Li, M., Ying, H., & Zhang, H. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.04.011 · Cited by 49
Impact of Epithelial Cell Shedding on Intestinal Homeostasis
Ngo, P. A., Neurath, M. F., & López-Posadas, R. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23084160 · Cited by 51
CYLD in health and disease
Marín‐Rubio, J. L., Raote, I., Inns, J., Dobson‐Stone, C., & Rajan, N. (2023) · Disease Models & Mechanisms · doi:10.1242/dmm.050093 · Cited by 51
Cell death programs in Yersinia immunity and pathogenesis
Philip, N. H., & Brodsky, I. E. (2012) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2012.00149 · Cited by 45
“MINI REVIEW ARTICLE published: 30 November 2012 doi: 10.3389/fcimb.2012.00149 Cell death programs in Yersinia immunity and pathogenesis”
BackgroundInfluential
The roles of ubiquitination in extrinsic cell death pathways and its implications for therapeutics
Seo, J., Kim, M. W., Bae, K., Lee, S. C., Song, J., & Lee, E. (2018) · Biochemical Pharmacology · doi:10.1016/j.bcp.2018.11.012 · Cited by 48
Necroptosis in inflammatory bowel disease and other intestinal diseases
Li, S., Ning, L., Lou, X., & Xu, G. (2018) · World Journal of Clinical Cases · doi:10.12998/wjcc.v6.i14.745 · Cited by 49
Novel insights into RIPK1 as a promising target for future Alzheimer’s disease treatment
Li, S., Qu, L., Wang, X., & Kong, L. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107979 · Cited by 51
A novel RIPK1 inhibitor reduces GVHD in mice via a nonimmunosuppressive mechanism that restores intestinal homeostasis
Yu, X., Ma, H., Li, B., Ji, Y., Du, Y., Liu, S., Li, Z., Hao, Y., Tian, S., Zhao, C., et al. (2022) · Blood · doi:10.1182/blood.2022017262 · Cited by 50
Excessive nucleic acid R-loops induce mitochondria-dependent epithelial cell necroptosis and drive spontaneous intestinal inflammation
Yang, X., Li, G., Lou, P., Zhang, M., Yao, K., Xiao, J., Chen, Y., Xu, J., Tian, S., Deng, M., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2307395120 · Cited by 48
“Moreover, it has been recognized that necroptotic activation drives spontaneous ileitis and/or colitis (9, 11–13).”
Ubiquitin-specific proteases in inflammatory bowel disease-related signalling pathway regulation
Chen, R., Pang, X., Li, L., Zeng, Z., Chen, M., & Zhang, S. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-04566-6 · Cited by 48
“Moreover, CYLD catalytic activity inhibition may prevent chronic inflammation and maintain physiological immune homoeostasis [89].”
Background
Baicalin inhibits necroptosis by decreasing oligomerization of phosphorylated MLKL and mitigates caerulein-induced acute pancreatitis in mice
Huang, Y., Liang, Q.-Q., Zhang, H., Chen, S., Xu, L., Zeng, B., Xu, R., Shi, F., Ouyang, D., Zha, Q., et al. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.108885 · Cited by 49
Inflammatory cell death in intestinal pathologies
Sharma, D., & Kanneganti, T. (2017) · Immunological Reviews · doi:10.1111/imr.12602 · Cited by 48
“Death domain and CYLD independent Apoptosis (162, 164) RelAIEC-KO Enteritis (paneth cell loss) cl- casp- 3 (+)/RIPK1- kinase activity dependent Apoptosis (162) RIPK1IEC-KO Intestinal inflammation TUNEL (+) and cl- casp- 3 (+)/Caspase- 8 dependent and RIPK3 independent Apoptosis (163) FADDIEC-KO Epithelial cell death N…”
BackgroundInfluential
Targeting P2Y14R protects against necroptosis of intestinal epithelial cells through PKA/CREB/RIPK1 axis in ulcerative colitis
Liu, C., Wang, H., Han, L., Zhu, Y., Ni, S., Zhi, J., Yang, X., Zhi, J., Tian, S., Li, H., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-46365-x · Cited by 51
Crosstalk between microbiota, pathogens and the innate immune responses
Günther, C., Josenhans, C., & Wehkamp, J. (2016) · International Journal of Medical Microbiology · doi:10.1016/j.ijmm.2016.03.003 · Cited by 50
The many faces of tumor necrosis factor signaling in the intestinal epithelium
Delgado, M. E., & Brunner, T. (2019) · Genes and Immunity · doi:10.1038/s41435-019-0057-0 · Cited by 45
Programmed cell death: NINJ1 and mechanisms of plasma membrane rupture
Ramos, S., Hartenian, E., & Brož, P. (2024) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2024.05.007 · Cited by 52
RIP1 kinase activity-dependent roles in embryonic development of Fadd-deficient mice
Liu, Y., Fan, C., Zhang, Y., Yu, X., Wu, X., Zhang, X., Zhao, Q., Zhang, H., Xie, Q., Li, M., et al. (2017) · Cell Death & Differentiation · doi:10.1038/cdd.2017.78 · Cited by 42
“Additionally, previous studies suggested that FADD could protect cells from RIP3dependent necroptosis and prevent upregulation of cytokine and chemokine expression in vivo.(46) Therefore, we examined cytokine and chemokine expression in fetal livers of FaddRip1 and littermate control Rip1 mice.”
Background
CNOT3 suppression promotes necroptosis by stabilizing mRNAs for cell death-inducing proteins
Suzuki, T., Kikuguchi, C., Sharma, S., Sasaki, T., Tokumasu, M., Adachi, S., Natsume, T., Kanegae, Y., & Yamamoto, T. S. (2015) · Scientific Reports · doi:10.1038/srep14779 · Cited by 45
Autophagy and necroptosis in cisplatin-induced acute kidney injury: Recent advances regarding their role and therapeutic potential
Alassaf, N., & Attia, H. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1103062 · Cited by 43
RIPK3 regulates p62–LC3 complex formation via the caspase-8-dependent cleavage of p62
Matsuzawa, Y., Oshima, S., Nibe, Y., Kobayashi, M., Maeyashiki, C., Nemoto, Y., Nagaishi, T., Okamoto, R., Tsuchiya, K., Nakamura, T., et al. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.11.075 · Cited by 44
Execution of RIPK3-regulated necrosis
Cai, Z., & Liu, Z.-G. (2014) · Molecular & Cellular Oncology · doi:10.4161/23723548.2014.960759 · Cited by 44
Mechanisms of RIPK3‐induced inflammation
Shlomovitz, I., Zargrian, S., & Gerlic, M. (2016) · Immunology and Cell Biology · doi:10.1038/icb.2016.124 · Cited by 43
cGAS-STING DNA-sensing in inflammatory bowel diseases
Dimitrov, G., Ryffel, B., Togbe, D., & Quesniaux, V. F. J. (2024) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2024.10.002 · Cited by 44
Epithelial mitochondrial fission-mediated PANoptosis is crucial for ulcerative colitis and its inhibition by saquinavir through Drp1
Ye, Z., Deng, M., Yang, Y., Song, Y., Weng, L., Qi, W., Ding, P., Huang, Y., Yu, C., Wang, Y., et al. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107538 · Cited by 46
Receptor Interactive Protein Kinase 3 Promotes Cisplatin-Triggered Necrosis in Apoptosis-Resistant Esophageal Squamous Cell Carcinoma Cells
Yang, X., Lin, Z., Zhao, N., Zhou, L., Liu, F., Cichacz, Z. A., Zhang, L., Zhan, Q., & Zhao, X. (2014) · PLoS ONE · doi:10.1371/journal.pone.0100127 · Cited by 43
“sis, leading to death during embryonic development [8,9].”
Background
Formation and removal of poly‐ubiquitin chains in the regulation of tumor necrosis factor‐induced gene activation and cell death
Kupka, S., Reichert, M., Dráber, P., & Walczak, H. (2016) · FEBS Journal · doi:10.1111/febs.13644 · Cited by 41
The deubiquitinating enzyme CYLD controls apical docking of basal bodies in ciliated epithelial cells
Eguether, T., Ermolaeva, M., Zhao, Y., Bonnet, M., Jain, A., Pasparakis, M., Courtois, G., & Tassin, A. (2014) · Nature Communications · doi:10.1038/ncomms5585 · Cited by 44
Self-citation
FADD expression is associated with regional and distant metastasis in squamous cell carcinoma of the head and neck
Pattje, W. J., Melchers, L. J., Slagter‐Menkema, L., Mastik, M. F., Schrijvers, M. L., Gibcus, J. H., Kluin, P. M., Chouvalova, O., van der Laan, B. F. A. M., Roodenburg, J. L. N., et al. (2013) · Histopathology · doi:10.1111/his.12174 · Cited by 41
The cytoplasmic nuclear receptor RARγ controls RIP1 initiated cell death when cIAP activity is inhibited
Xu, Q., Jitkaew, S., Choksi, S., Kadigamuwa, C., Qu, J., Choe, M., Jang, J., Liu, C., & Liu, Z.-G. (2017) · Nature Communications · doi:10.1038/s41467-017-00496-6 · Cited by 42
Potent and selective inhibitors of receptor-interacting protein kinase 1 that lack an aromatic back pocket group
Hamilton, G. L., Chen, H., Deshmukh, G. S., Eigenbrot, C. W., Fong, R., Johnson, A., Kohli, P. B., Lupardus, P. J., Liederer, B. M., Ramaswamy, S., et al. (2019) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2019.04.014 · Cited by 41
Traditional herbal formula Wu-Mei-Wan alleviates TNBS-induced colitis in mice by inhibiting necroptosis through increasing RIPK3 O-GlcNAcylation
Wu, F., Shao, Q., Cheng, Z., Xiong, X., Fang, K., Zhao, Y. Q., Dong, R., Xu, L., Lu, F., & Chen, G. (2021) · Chinese Medicine · doi:10.1186/s13020-021-00493-4 · Cited by 41
Inhibition of Lung Cancer by 2-Methoxy-6-Acetyl-7-Methyljuglone Through Induction of Necroptosis by Targeting Receptor-Interacting Protein 1
Sun, W. C., Yu, J. Z., Gao, H., Wu, X., Wang, S., Hou, Y., Lu, J., & Chen, X. (2018) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7376 · Cited by 40
“Especially, the feasibility of ﬁghting cancer with necroptotic inducers remains largely unknown, and there are concerns and controversies on the proinﬂammatory effect of necroptosis in vivo (9, 14, 41).”
Convergent Loss of the Necroptosis Pathway in Disparate Mammalian Lineages Shapes Viruses Countermeasures
Águeda-Pinto, A., Alves, L. Q., Neves, F., McFadden, G., Jacobs, B. L., Castro, L. F. C., Rahman, M. M., & Esteves, P. J. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.747737 · Cited by 40
“Mouse-model experiments identified keratinocyte necroptosis as a trigger of skin inflammation (54) and a correlation between necroptosis and intestinal inflammation has also been established (55, 56).”
Background
MyD88 mediates the decision to die by apoptosis or necroptosis after UV irradiation
Harberts, E. M., Fishelevich, R., Liu, J., Atamas, S. P., & Gaspari, A. A. (2013) · Innate Immunity · doi:10.1177/1753425913501706 · Cited by 38
“Our data are consistent with evolving literature that describes necroptosis as a default cell death pathway in the absence of apoptosis.(1,12,20,36) It has recently been shown that RIP1 controls and induces TNF-a production during necroptosis.”
BackgroundResult
Distinct cytoprotective roles of pyruvate and ATP by glucose metabolism on epithelial necroptosis and crypt proliferation in ischaemic gut
Huang, C., Kuo, W., Huang, C., Lee, T., Chen, C., Peng, W., Lu, K., Yang, C., & Yu, L. C. (2016) · The Journal of Physiology · doi:10.1113/jp272208 · Cited by 39
“RIP1/3-mediated necroptosis in intestinal epithelial cells has been documented in murine models of experimental enterocolitis and in patients with inflammatory bowel disease (Gunther et al. 2011; Welz et al. 2011; Pierdomenico et al. 2014), as well as in in vitro epithelial cell cultures exposed to hypoxic stress or c…”
Background
Current and Emerging Biomarkers of Cell Death in Human Disease
Li, K., Wu, D., Chen, X., Zhang, T., Zhang, L., Yi, Y., Miao, Z., Jin, N., Bi, X., Wang, H., et al. (2014) · BioMed Research International · doi:10.1155/2014/690103 · Cited by 40
“Necrosis [110–112]”
Cellular Dynamics of Fas-Associated Death Domain in the Regulation of Cancer and Inflammation
Ranjan, K., & Pathak, C. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25063228 · Cited by 36
“The multifaceted role of FADD has also been documented in RIP1-and RIP3-dependent necroptosis signaling [18,19].”
Background
Protective effect of NSA on intestinal epithelial cells in a necroptosis model
Dong, W., Zhang, M., Zhu, Y., Chen, Y., Zhao, X., Li, R., Zhang, L., Ye, Z., & Liang, X. (2017) · Oncotarget · doi:10.18632/oncotarget.21418 · Cited by 39
“Mice with a conditional deletion of caspase-8 or FADD in the intestinal epithelium spontaneously undergo intestinal necroptosis and develop colitis [9, 10].”
BackgroundResult

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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

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

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Citations

Cites

Cited by

Related

Metadata

Record

About these checks