Cell death in the intestinal epithelium has to be tightly controlled. Excessive or misplaced epithelial cell death can result in barrier dysfunction and, as a consequence thereof, uncontrolled translocation of components of the microbial flora from the lumen into the bowel wall. Susceptibility to gastrointestinal
infections or chronic
inflammation of the gut, as observed in patients with
inflammatory bowel disease, can be the result of such dysregulation. Conversely, defects in cell death initiation might lead to an irregular accumulation of epithelial cells and cause
intestinal cancer development. Until recently, activation of
caspases in the intestinal epithelium was considered as a potential contributor to barrier dysfunction and as a pathogenic factor in the development of intestinal
inflammation. Thus blocking of
caspases appeared to be a potential therapeutic option for patients with
inflammatory bowel disease. Recent studies on necroptosis however demonstrated that also inhibition of
caspases can cause barrier dysfunction and intestinal
inflammation.
Caspase-8 on top of its functions in the extrinsic apoptosis pathway also controls necroptosis and turns out to be an essential molecule in regulating tissue homeostasis in the gut. Epithelial
caspase-8 therefore emerges as a checkpoint not only of cell survival and cell death, but also as a regulator of the mode of cell death. According to this model, both excessive activity as well as a lack of activity of
caspase-8 results in epithelial cell death and intestinal
inflammation and
caspase-8 needs to be tightly controlled to warrant tissue homeostasis in the gut.