Details

Autor(en) / Beteiligte

• Weinlich, Ricardo
• Oberst, Andrew
• Dillon, Christopher P.
• Janke, Laura J.
• Milasta, Sandra
• Lukens, John R.
• Rodriguez, Diego A.
• Gurung, Prajwal
• Savage, Chandra
• Kanneganti, Thirumala D.
• Green, Douglas R.

Titel

Protective Roles for Caspase-8 and cFLIP in Adult Homeostasis

Ist Teil von

• Cell reports (Cambridge), 2013-10, Vol.5 (2), p.340-348

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2013

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.