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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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“Recently, in a mouse model of inflammation in the skin that is induced by SHARPIN-deficiency, RIPK1 kinase-dead mice displayed significant rescue,(20) whereas in the models of gut inflammation the kinase activity of RIPK1 did not promote severe colitis.(24,41) Further, it was shown that RIPK1 and RIPK3 are found in a…”
BackgroundNFATc1 supports imiquimod-induced skin inflammation by suppressing IL-10 synthesis in B cells
Alrefai, H., Muhammad, K., Rudolf, R., Pham, D. A. T., Klein‐Hessling, S., Patra, A. K., Avots, A., Bukur, V., Şahin, U., Tenzer, S., et al. (2016) · Nature Communications · doi:10.1038/ncomms11724 · Cited by 74
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“Notably, RIP3 is highly abundant in immune cells (Lu and Walsh, 2012), keratinocytes (Dannappel et al, 2014), and intestinal epithelial cells (Dannappel et al, 2014; Takahashi et al, 2014).”
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BackgroundThe necroptosis cell death pathway drives neurodegeneration in Alzheimer’s disease
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“3) [35].”
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“This massive IEC apoptosis appears to be due to hyper-responsiveness of the intestinal epithelium to TNF/TNFR1 signaling because combined deletion of TNFR1 prevented the intestinal pathology in both Ripk1 / and Ripk1 mice.(56,57) In this regard, it is interesting that RIPK1 is ubiquitinated by cIAP1 and 2 in the TNFR…”
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Self-citationThe potential role of necroptosis in clinical diseases (Review)
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“conditional deletion of RIP1 in kera‐ tinocytes or intestinal epithelial cells suggested RIP1 plays an essential role in maintaining epithelial homeostasis (29,30).”
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“RIPK1 regulates apoptosis and necroptosis via kinase-dependent and -independent functions, which are essential for cell fate and inflammation (Dannappel et al., 2014; Rickard et al., 2014).”
BackgroundRIPK1 prevents TRADD-driven, but TNFR1 independent, apoptosis during development
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Zeb2 drives invasive and microbiota-dependent colon carcinoma
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Virulence Factors of Mycobacterium tuberculosis as Modulators of Cell Death Mechanisms
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“In support of this, the conditional deletion of RIPK1 in intestinal epithelial cells (IECs) was reported to result in apoptosis of IECs and intestinal inflammation (9, 10), suggesting that RIPK1 maintains epithelial homeostasis by inhibiting apoptosis in the intestine (9).”
BackgroundThe Molecular Links between Cell Death and Inflammasome
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Self-citationAn intestinal organoid–based platform that recreates susceptibility to T-cell–mediated tissue injury
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“Therefore, inhibition of necroptosis is a potentially effective treatment strategy for myriad diseases involving inflammation and cell death [25].”
BackgroundA20 and ABIN-1 synergistically preserve intestinal epithelial cell survival
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“RIPK1 binds caspase 8, and RIPK1’s kinase activity can support both apoptotic and necroptotic death (Dondelinger et al., 2013; Dannappel et al., 2014; Vlantis et al., 2016; Kondylis et al., 2017).”
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The RIPK1 death domain restrains ZBP1- and TRIF-mediated cell death and inflammation
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Self-citationMolecular Cell Biology of Apoptosis and Necroptosis in Cancer
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“Whereas it seemed to be an established concept that necroptosis depends on the formation of RIPK1/RIPK3 dimers,((7,8)) it was recently suggested that RIPK1 might not mediate, but rather inhibit, necroptosis in gut or skin epithelial cells.((44)) Our present data that IKKa/b/ RIPK1 mice showed a strong reduction in nec…”
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STING induces ZBP1-mediated necroptosis independently of TNFR1 and FADD
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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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