Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2041960 | Cell Reports | 2013 | 9 Pages |
•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
SummaryCaspase-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.
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