Multiple roles of caspase-8 in cell death, inflammation, and innate immunity

Caspase-8 is an apical caspase involved in the programmed form of cell death called apoptosis that is critically important for mammalian development and immunity. Apoptosis was historically described as immunologically silent in contrast to other types of programmed cell death such as necroptosis or pyroptosis. Recent reports suggest considerable crosstalk between these different forms of cell death. It is becoming increasingly clear that caspase-8 has many non-apoptotic roles, participating in multiple processes including regulation of necroptosis (mediated by receptor-interacting serine/threonine kinases, RIPK1-RIPK3), inflammatory cytokine expression, inflammasome activation, and cleavage of IL-1β and gasdermin D, and protection against shock and microbial infection. In this review, we discuss the involvement of caspase-8 in cell death and inflammation and highlight its role in innate immune responses and in the relationship between different forms of cell death. Caspase-8 is one of the central components in this type of crosstalk.