Protective Roles for Caspase-8 and cFLIP in Adult Homeostasis

Abstract

Summary Caspase-8 or cFLIP deficiency leads to embryonic lethality in mice due to defects in endothelial tissues. Caspase-8−/−, RIPK3−/−, but not cFLIP−/−, 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. Acute loss of cFLIP in the skin produces a similar phenotype, which, however, 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.

Die another way – non-apoptotic mechanisms of cell death

“…Recent data has clearly shown a vital role for RIPK3 during embryogenesis, but this is only revealed in the absence of caspase-8 or FADD. In adult mice, disabling the ability of caspase-8 to inhibit RIPK3 (by either caspase-8 or FLIP deletion) in specific organs also leads to RIPK3-dependent inflammation and necrosis in the intestine and skin (Bonnet et al, 2011;Panayotova-Dimitrova et al, 2013;Weinlich et al, 2013;Welz et al, 2011). Recent studies also argue that RIPK3 can directly induce inflammation even in the absence of cell death, thereby complicating direct implication of RIPK3-dependent necroptosis in any given process (Kang et al, 2013;Vince et al, 2012).…”

Characterization of RIPK3-mediated phosphorylation of the activation loop of MLKL during necroptosis

“…[1][2][3] The function of RIPK3 to promote necroptosis can be induced by the activity of receptor-interacting protein kinase-1 (RIPK1), 4 and is antagonized by the proteolytic activity of a complex formed by RIPK1, FADD, caspase-8 and c-FLIP L . [5][6][7][8][9][10] Inactive RIPK1 functions to inhibit RIPK3 activation, even under conditions in which RIPK3 is activated independently of RIPK1. [11][12][13] These complex interactions help to account for the lethal effects of ablating FADD, caspase-8 or RIPK1.…”

The MLKL Channel in Necroptosis Is an Octamer Formed by Tetramers in a Dyadic Process

“…Studies in recent years have demonstrated the involvement of necroptosis in a number of pathophysiological processes, such as atherosclerosis (6), skin inflammation (7)(8)(9), chronic intestinal inflammation (10, 11), Gaucher's disease (12), acute liver injury (13,14), and heightened intestinal inflammation (15).…”