Journal article
Protective Roles for Caspase-8 and cFLIP in Adult Homeostasis
Cell reports (Cambridge), Vol.5(2), pp.340-348
10/31/2013
DOI: 10.1016/j.celrep.2013.08.045
PMCID: PMC3843376
PMID: 24095739
Abstract
Caspase-8 or cellular FLICE-like inhibitor protein (cFLIP) deficiency leads to embryonic lethality in mice due to defects in endothelial tissues. Caspase-8−/− and receptor-interacting protein kinase-3 (RIPK3)−/−, but not cFLIP−/− and RIPK3−/−, double-knockout animals develop normally, indicating that caspase-8 antagonizes the lethal effects of RIPK3 during development. Here, we show that the acute deletion of caspase-8 in the gut of adult mice induces enterocyte death, disruption of tissue homeostasis, and inflammation, resulting in sepsis and mortality. Likewise, acute deletion of caspase-8 in a focal region of the skin induces local keratinocyte death, tissue disruption, and inflammation. Strikingly, RIPK3 ablation rescues both phenotypes. However, acute loss of cFLIP in the skin produces a similar phenotype that is not rescued by RIPK3 ablation. TNF neutralization protects from either acute loss of caspase-8 or cFLIP. These results demonstrate that caspase-8-mediated suppression of RIPK3-induced death is required not only during development but also for adult homeostasis. Furthermore, RIPK3-dependent inflammation is dispensable for the skin phenotype.
[Display omitted]
•Acute deletion of caspase-8 or cFLIP in the gut or skin disrupts tissue homeostasis•Ablation of RIPK3 rescues the damaging effects of acute caspase-8, but not cFLIP, loss•RIPK3-mediated inflammation is dispensable for the skin damage by acute cFLIP loss•Neutralization of TNF rescues from the effects of acute loss of caspase-8 or cFLIP
In this study, Green and colleagues show that acute loss of caspase-8 in the gut or the skin can induce a TNF-dependent, RIPK3-mediated loss of tissue homeostasis and inflammation, demonstrating that RIPK3 function is tightly regulated in adult tissues. Strikingly, the authors show that loss of cFLIP in RIPK3-deficient background induces a similar phenotype, suggesting that loss of tissue barrier function, rather than the type of cell death (necroptosis or apoptosis), defines the onset of disease.
Details
- Title: Subtitle
- Protective Roles for Caspase-8 and cFLIP in Adult Homeostasis
- Creators
- Ricardo Weinlich - Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USAAndrew Oberst - Department of Immunology, University of Washington, Seattle, WA 98109, USAChristopher P Dillon - Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USALaura J Janke - Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USASandra Milasta - Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USAJohn R Lukens - Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USADiego A Rodriguez - Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USAPrajwal Gurung - Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USAChandra Savage - Animal Resource Center, St. Jude Children’s Research Hospital, Memphis, TN 38105, USAThirumala D Kanneganti - Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USADouglas R Green - Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Resource Type
- Journal article
- Publication Details
- Cell reports (Cambridge), Vol.5(2), pp.340-348
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.celrep.2013.08.045
- PMID
- 24095739
- PMCID
- PMC3843376
- ISSN
- 2211-1247
- eISSN
- 2211-1247
- Language
- English
- Date published
- 10/31/2013
- Academic Unit
- Infectious Diseases; Internal Medicine
- Record Identifier
- 9984094570302771
Metrics
15 Record Views