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RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis
Open accessAbstract
Necroptosis has emerged as an important pathway of programmed cell death in embryonic development, tissue homeostasis, immunity and inflammation. RIPK1 is implicated in inflammatory and cell death signalling and its kinase activity is believed to drive RIPK3-mediated necroptosis. Here we show that kinase-independent scaffolding RIPK1 functions regulate homeostasis and prevent inflammation in barrier tissues by inhibiting epithelial cell apoptosis and necroptosis. Intestinal epithelial cell (IEC)-specific RIPK1 knockout caused IEC apoptosis, villus atrophy, loss of goblet and Paneth cells and premature death in mice. This pathology developed independently of the microbiota and of MyD88 signalling but was partly rescued by TNFR1 (also known as TNFRSF1A) deficiency. Epithelial FADD ablation inhibited IEC apoptosis and prevented the premature death of mice with IEC-specific RIPK1 knockout. However, mice lacking both RIPK1 and FADD in IECs displayed RIPK3-dependent IEC necroptosis, Paneth cell loss and focal erosive inflammatory lesions in the colon. Moreover, a RIPK1 kinase inactive knock-in delayed but did not prevent inflammation caused by FADD deficiency in IECs or keratinocytes, showing that RIPK3-dependent necroptosis of FADD-deficient epithelial cells only partly requires RIPK1 kinase activity. Epidermis-specific RIPK1 knockout triggered keratinocyte apoptosis and necroptosis and caused severe skin inflammation that was prevented by RIPK3 but not FADD deficiency. These findings revealed that RIPK1 inhibits RIPK3-mediated necroptosis in keratinocytes in vivo and identified necroptosis as a more potent trigger of inflammation compared with apoptosis. Therefore, RIPK1 is a master regulator of epithelial cell survival, homeostasis and inflammation in the intestine and the skin.
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“Likewise, the absence of Ripk1 from keratinocytes promotes spontaneous necroptosis and consequent cutaneous inflammation, which can be prevented by the co-deletion of Ripk3, Mlkl, or Zbp1 but not Fadd [440, 502].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [502]
In the citing paper
“Conditional knockout mouse models demonstrate the key role of RIPK1 for the preservation of intestinal and cutaneous homeostasis and survival [502, 503].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [502]
In the citing paper
“In particular, mice lacking Ripk1 in intestinal epithelial cells display increased rates of spontaneous CASP8-driven apoptosis and develop severe inflammatory lesions leading to premature death, a detrimental phenotype that can be prevented by co-deleting Fadd or (to a lesser degree) Tnfrsf1a [502].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [502]
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Identification of Piperlongumine as Potent Inhibitor of Necroptosis
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BackgroundFunctions of the RIP kinase family members in the skin
Urwyler-Rösselet, C., Tanghe, G., Devos, M., Hulpiau, P., Saeys, Y., & Declercq, W. (2023) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-04917-2 · Cited by 11
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BackgroundInfluentialThe E3 ligase Itch knockout mice show hyperproliferation and wound healing alteration
Miraglia, A. G., Cianfarani, F., Cattani, C., Lena, A. M., Serra, V., Campione, E., Terrinoni, A., Zambruno, G., Odorisio, T., Daniele, N. D., et al. (2015) · FEBS Journal · doi:10.1111/febs.13514 · Cited by 9
ABIN1 Inhibits Inflammation through Necroptosis-Dependent Pathway in Ulcerative Colitis
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“[27] found that mice with IECs conditional deletion of RIPK1 gene (RIPK1 IEC-KO) would die within 4 weeks after birth, accompanied by inflammatory infiltration of intestinal tissue.”
BackgroundThe roles of long non-coding RNAs in the necroptotic signaling of colon cancer cells
Bozgeyi̇k, E., Bağış, H., Bozgeyik, İ., & Kocahan, S. (2023) · Molecular Biology Reports · doi:10.1007/s11033-023-08441-1 · Cited by 9
“1 3 necroptotic signaling contributes to the onset of a number of infectious, inflammatory, and degenerative disorders such as chronic intestinal inflammation [6, 7], non-alcoholic steatohepatitis [8, 9], inflammatory skin disease [10, 11], amyotrophic lateral sclerosis [12], and multiple sclerosis [13].”
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Discovery of Sibiriline derivatives as novel receptor-interacting protein kinase 1 inhibitors
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“RIPK1, a death domain-containing serine/threonine protein kinase, acts as regulator of apoptosis and necroptosis downstream of TNF-, TRAIL, and TLRs, and skin inflammation.(68) Recent studies have shown that keratinocytes in psoriatic lesions are highly sensitive to TRAIL signaling by RIPK1downregulation.”
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BackgroundRIPK1 autophosphorylation at S161 mediates cell death and inflammation
Koerner, L., Li, X., Silnov, E., Laurien, L., & Pasparakis, M. (2025) · The Journal of Experimental Medicine · doi:10.1084/jem.20250279 · Cited by 8
“…acts as a scaffold to induce pro-survival and pro-inflammatory signaling, a function that is critical for mouse development and tissue homeostasis (Dannappel et al., 2014; Dillon et al., 2014; Imai et al., 2024; Kaiser et al., 2014; Kelliher et al., 1998; Lin et al., 2016; Newton et al., 2016b;…”
Self-citationSkin immunity and inflammation: cellular interactions and communication
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“Phosphorylated MLKL oligomerizes and destroys the permeability of the cell plasma membrane, causing DAMPs, inflammatory factors, Ca2+ and Na+ to flow into the cell, leading to local inflammation and cell death (Dannappel et al. 2014; Rathkey et al. 2018; Deroo et al. 2020).”
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“…deletion of apoptotic components—Fas-associated protein with death domain (FADD E-KO ) [39] or caspase-8 (Caspase-8 E-KO ) [40,41]—or apoptotic/necroptotic components—receptor-interacting protein kinases (RIPKs) 1 (RIPK1 E-KO ) [42]—experienced the development of inflammatory skin lesions.”
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“Aberrant levels of MLKL-dependent cell death contribute to disease in several genetic and experimental mouse models (Anderton et al., 2017; Dannappel et al., 2014; Hockendorf et al., 2016; Newton et al., 2016; Rickard et al., 2014a; Rickard et al., 2014b).”
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Self-citationVery-early-onset Inflammatory Bowel Disease in an Infant with a Partial RIPK1 Deletion
Kırşaçlıoğlu, C. T., Frohne, A., Kuloğlu, Z., Kristofersdottir, I., Demir, E., Altuntaş, C., Haskoloğlu, Z. Ş., Çobanoğlu, N., Kendirli, T., Özdemir, H., et al. (2024) · Journal of Clinical Immunology · doi:10.1007/s10875-024-01707-8 · Cited by 5
“Whereas intestinal cell apoptosis seems to play a crucial role in mice, the symptoms in RIPK1 deficient humans are predominantly mediated by dysregulated immune signalling [ 11 , 12 ].”
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“Broilers under intensive production conditions are easily infected by pathogenic microorganisms, which often induce immune stress in the chickens (51), causing damage to the intestinal mucosa (52), intestinal villi atrophy (53), increased crypt depth and intestinal permeability (54).”
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“Furthermore, the balance between cell proliferation and death of intestinal epithelial cells is a critical factor in the maintenance of gut homeostasis [22], and increased apoptosis, in particular, can be a risk factor leading to intestinal epithelial barrier dysfunction [27, 28].”
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Hou, B., Huang, H., Li, Y.-Q., Liang, J., Xi, Z., Jiang, X., Liu, L., & Li, E. (2022) · Cell Death Discovery · doi:10.1038/s41420-022-01106-1 · Cited by 5
“Additionally, RIP1 was certainly found to play a regulatory role other than necroptosis; indeed, it has been found to maintain epithelial homeostasis by inhibiting both apoptosis and necroptosis [46].”
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“TNFα induces the subsequent activation of RIPK3 and MLKL, whereas IFNγ acts through STAT3-protein kinase to activate necroptosis [46].”
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“…and associated skin in fl ammation in epidermal cell-speci fi c RIPK1 knockout mice can be effectively inhibited by the deletion of RIPK3 or MLKL [26], suggesting that RIPK1 plays a crucial role in maintaining the homeostasis and survival of epidermal cells, highlighting the complexity of its…”
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“Furthermore, the clinical manifestations observed in RIPK1-deficient individuals closely resemble the systemic inflammatory phenotype reported in RIPK1-deficient mice 105,106,144,145 .”
Programmed cell death of keratinocytes: an active driver in psoriasis
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Recent advances in the role of gasotransmitters in necroptosis
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Regulated necrosis at the crossroads of liver inflammation and cancer development
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Inhibition of TBK1/IKKe mediated RIPK1 phosphorylation sensitizes tumors to immune cell killingPreprint
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Targeting RIPK1 to modulate cell death and tumour microenvironment in cancer therapy
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“48 in immune cells, deletion or mutation of the deubiquitinating enzyme OtuD1 leads to excessive K63-linked ubiquitination at lysine 627 of RiPK1, resulting in hyperactivation of the NF-κB signalling pathway and contributing to intestinal inflammation.”
cGAS-IFN-I responses by extracting nuclear DNA from dying cells via nucleocytosis
Negishi, H., Wada, Y., Shirasaki, Y., Hayashi, T., Kubota, Y., Iwasaki, T., Kurosawa, M., Ban, T., Muto, D., Suenaga, Y., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-68839-w · Cited by 3
“Mlkl -/- mice were kindly provided by Dr. Manolis Pasparakis 63 .”
RIPK1 protects epithelial cells
Baumann, K. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3876 · Cited by 2
Obata, Y., & Hase, K. (2015) · Inflammation and Regeneration · doi:10.2492/inflammregen.35.003 · Cited by 2
Jung, S.-Y., Park, J., Jeong, J., Song, K., Ahn, J., Hwang, S., Kim, J., Park, J.-K., Lim, D., & Song, J. Y. (2022) · PubMed Central · Cited by 2
The fate and function of non-coding RNAs during necroptosis
Bozgeyi̇k, E., Elek, A., Gocer, Z., & Bozgeyik, İ. (2024) · Epigenomics · doi:10.1080/17501911.2024.2354653 · Cited by 2
A guardian angel of cell integrity
Chan, F. K.-M. (2014) · Nature · doi:10.1038/513038a · Cited by 2
RIP(K)ing away immunotherapy resistance
Patel, M. A., & Tavazoie, S. F. (2022) · Immunity · doi:10.1016/j.immuni.2022.03.010 · Cited by 2
Role of hepatocyte RIPK1 in maintaining liver homeostasis during metabolic challengesPreprint
Zhang, W., Liu, H., Zhang, D., Yi, Y., Tao, L., Zhu, Y., Huang, S., Zhao, X., Shao, Q., Li, P., et al. (2024) · eLife · doi:10.7554/elife.96798 · Cited by 2
Reduction of intestinal RIPK1 ameliorates HFD-induced metabolic disorders in female mice
Yuan, Y., Hu, X., Guo, C., Xu, Y., Li, S., Wen, W., Hu, X., Zeng, F., Cui, W., Chen, W., et al. (2025) · iScience · doi:10.1016/j.isci.2025.111906 · Cited by 1
“As in prior studies, 15,16 we found that almost all of the mice homozygous for IEC Ripk1 -knockout ( Ripk1 IEC (cid:1) / (cid:1) ) died within one week after birth; only very few Ripk1 IEC (cid:1) / (cid:1) mice could survivetoafew weeks,buttheirbodysizeweremuchsmallerthan their wild type (WT)…”
Inhibition of TBK1/IKKε mediated RIPK1 phosphorylation sensitizes tumors to immune cell killing
Piskopou, A., Vredevoogd, D. W., Kong, X., Peeper, D. S., Altelaar, M. A. F., & Stecker, K. E. (2025) · Cell Death Discovery · doi:10.1038/s41420-025-02841-x · Cited by 4
Dismantling the Necroptotic Engine: An Oral Theranostic Nanosponge for Ulcerative Colitis
Xiao, Y., Chen, X., Liao, J., Wang, J., Lü, L., Chen, H., Niu, C., & Wang, M. (2026) · Advanced Materials · doi:10.1002/adma.202516297 · Cited by 1
“At the heart of this pathway lies the receptor-interacting protein kinase 1 (RIPK1), a central signaling node that dictates cell fate [34, 35].”
Unlocking the potential of TNF: From biologic agents to small-molecule inhibitors
Huang, Y., Mu, L., Qu, Y., & Liu, Y. (2026) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2026.118780 · Cited by 1
Mechanisms, regulation and clinical relevance of necroptosis
Yang, Y., Jiao, H., & Xu, D. (2026) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-026-01002-x · Cited by 2
“Mouse models with RIPK1, FADD or caspase-8 deficiency manifest with inflammatory conditions, which are driven largely by RIPK3-dependent and MLKL-dependent necroptosis 98,99,109,115,120,198,234 .”
2014: Signaling Breakthroughs of the Year
Berndt, J. D., & Wong, W. (2015) · Science Signaling · doi:10.1126/scisignal.aaa4696 · Cited by 1
Chemokines and Traffic of White Blood Cells
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Analysis of Gene Expression Data of RPL10 Mutant T-Cell Leukemia by SEMsubPA
Pepe, D., & Keersmaecker, K. D. (2018) · IEEE International Conference on Bioinformatics and Biomedicine (BIBM) · doi:10.1109/bibm.2018.8621215 · Cited by 1
“It is important for the cell survival, homeostasis and inflammation [27].”
BackgroundHousing conditions affect enterocyte death mode and turnover rate in mouse small intestine
Matsuoka, Y., & Tsujimoto, Y. (2023) · Scientific Reports · doi:10.1038/s41598-023-47660-1 · Cited by 1
Role of hepatocyte RIPK1 in maintaining liver homeostasis during metabolic challenges
Zhang, W., Liu, H., Zhang, D., Yi, Y., Tao, L., Zhu, Y., Huang, S., Zhao, X., Shao, Q., Li, P., et al. (2025) · eLife · doi:10.7554/elife.96798.3 · Cited by 1
The Effect of TNF-α on the Regulation of Epithelial Function in Inflammatory Bowel Disease
Tsuchiya, K. (2015) · Frontiers of gastrointestinal research · doi:10.1159/000381380 · Cited by 1
The Immunology of Transplantation
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Dissection of TLR4-Induced Necroptosis Using Specific Inhibitors of Endocytosis and P38 MAPK
Ariana, A. (2017) · uO Research (University of Ottawa) · doi:10.20381/ruor-20249 · Cited by 1
“…there are mutual interactions among various proteins that participate in cell survival, cell death, and inflammation (Christofferson and Yuan, 2010; Dannappel et al., 2014; Galluzzi and Kroemer, 2008; Nikoletopoulou et al., 2013; Pasparakis and Vandenabeele, 2015; Vanden Berghe et al., 2015; Zhou…”
BackgroundEckhart, L. (2018) · Wiley eBooks · doi:10.1002/9781119432463.ch9 · Cited by 1
Excessive apoptosis of naïve T cells resulting hyperactivation as a cause of mammalian agingPreprint
Wang, L., Zhang, X., Zhang, H., Lu, K., Li, M., Li, X., Ou, Y., Zhao, X., Wu, X., Wu, X., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.02.24.529806 · Cited by 1
Zheng, C., Hu, W., Nan, Q., Huang, Y., Zhang, H., Qiu, X., Tang, Z., Shi, J., & Huang, Y. (2025) · Research Square · doi:10.21203/rs.3.rs-6212184/v1 · Cited by 1
Bernard, L., Neil, J. A., Kim, K., Heaney, T. G., Miller, B. M., Moon, D., Lubkin, A., Dumont, A., Torres, V. J., Axelrad, J. E., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.01.10.698817 · Cited by 1
“Type I Interferons (IFN-α/β) and type III interferons (IFN-λs) are best known for their antiviral functions downstream of Janus kinases (JAK) and signal transducer and activator of transcription proteins (STAT) upon receptor engagement.”
InfluentialTRIM27 in HSV-1 Infection: A Story of Loss and Death
Conwell, S. E. (2015) · Digital Access to Scholarship at Harvard (DASH) (Harvard University)
Barrier regulation: tolerance stops at cell death
Pott, J., Maloy, K. J., & Ízcue, A. (2016) · Nature Immunology · doi:10.1038/ni.3418
The Roles of Necroptosis in the Pathogenesis of Staphylococcus aureus Infection
Kitur, K. (2016) · doi:10.7916/d8dr2vk2
“43 Keratinocytes can undergo apoptosis (as part of the natural differentiation process) or necroptosis (such as during infection or autoimmune disease), and the balance between the two is tightly regulated by RIPK3 and caspase-8 (61).”
BackgroundHolding RIPK1 on the Ubiquitin Leash in TNFR1
Peltzer, S., Darding, M., & Walczak, H. (2016)
VDR-RIPK1 Interaction and its Implications in Cell Death and Cancer Intervention
Quarni, W. (2016) · Digital Commons - University of South Florida (University of South Florida)
Nouvelles voies de mort cellulaire des hépatocytes
Filliol, A. A., Seyec, J. L., & Samson, M. (2017)
Polo, A., Nittoli, C., Crispo, A., Langastro, T., Cocco, S., Severino, L., Laurentiis, M. D., Ciliberto, G., Montella, M., Budillon, A., et al. (2017) · Molecular BioSystems · doi:10.1039/c7mb00489c
Exploration of immunogene in colon cancer recurrence
Sun, Q.-R., Chen, Y., Yuan, S., & Liao, J. (2018) · Oncotarget · doi:10.18632/oncotarget.24218
A20 and ABIN-1 team up against intestinal epithelial cell death
Cadwell, K. (2018) · The Journal of Experimental Medicine · doi:10.1084/jem.20180953
Verdauung und Darmerkrankungen
Fegerl, S. P., Sartor, H., & Witasek, A. (2019) · Springer eBooks · doi:10.1007/978-3-662-58111-7_6
Wang, S., Xu, E., Ge, R., Jia, H., Fan, Y., Hu, M., Jin, S., Guan, T., Ren, X., & Liu, Y. (2020) · Research Square · doi:10.21203/rs.3.rs-56391/v1
The Potential Value of Plasma Receptor Interacting Protein 3 for Neonatal Sepsis DiagnosisPreprint
Gao, C., Feng, Z., Wang, L., Zhao, X., Fu, K., Ma, S., Yang, Z., Wang, S., & Yu, S. (2021) · Research Square · doi:10.21203/rs.3.rs-300543/v1
“At present, the mechanisms of necrosis mainly covers programmed necrosis, ferroptosis, inflammatory necrosis and other pathways [14, 20-22] .”
BackgroundNovel RIPK1 Mutations Causing Infantile-onset IBD with Inflammatory and Fistulizing FeaturesPreprint
Sultan, M. I., Adawi, M., Kol, N., McCourt, B. T., Adawi, I., Werner, L., Lev, A., Snapper, S. B., Barel, O., Konnikova, L., et al. (2022) · Research Square · doi:10.21203/rs.3.rs-1347173/v1
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Metadata
- Authors
- Dannappel, M., Vlantis, K., Kumari, S., Polykratis, A., Kim, C., Wachsmuth, L., Eftychi, C., Lin, J., Corona, T., Hermance, N., Zelic, M., Kirsch, P., Basic, M., Bleich, A., Kelliher, M., & Pasparakis, M.
- Affiliations
- University of Cologne (DE)
- University of Massachusetts Chan Medical School (US)
- Universität Ulm (DE)
- Medizinische Hochschule Hannover (DE)
- Corresponding author
- Pasparakis, Manolis
- ORCID
- Venue
- Nature
- Published
- 2014-08-17
- Volume
- 513
- Issue
- 7516
- Pages
- 90-94
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4206266
- OpenAlex
- W1985231277
- Cited by
- 534
- References
- 47
- Citations by year
- 2026: 21 · 2025: 33 · 2024: 46 · 2023: 36 · 2022: 56 · 2021: 47 · 2020: 47 · 2019: 49 · 2018: 44 · 2017: 33 · 2016: 59 · 2015: 49 · 2014: 14
- FWCI
- 21.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI075118, T32AI095213)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- RIPK1, necroptosis, apoptosis, epithelial homeostasis, FADD, caspase-8, RIPK3, intestinal epithelium, skin inflammation, keratinocytes, TNFR1, barrier tissues, inflammation, programmed cell death, Paneth cells, goblet cells, villous atrophy, intestinal inflammation
- MeSH terms
- Animals, Cell Survival, Epithelial Cells, Female, Homeostasis, Inflammation, Intestinal Mucosa, Intestines, Male, Necrosis, Skin, Keratinocytes, Apoptosis, Mice, Knockout, Paneth Cells, Receptors, Tumor Necrosis Factor, Type I, Mice, Caspase 8, Fas-Associated Death Domain Protein, Receptor-Interacting Protein Serine-Threonine Kinases, Myeloid Differentiation Factor 88
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