Regulation of Caspase-8 Activity at the Crossroads of Pro-Inflammation and Anti-Inflammation

Abstract

Caspase-8 has been classified as an apoptotic caspase, and its initial definition was an initiator of extrinsic cell death. During the past decade, the concept of caspase-8 functioning has been changed by findings of its additional roles in diverse biological processes. Although caspase-8 was not originally thought to be involved in the inflammation process, many recent works have determined that caspase-8 plays an important role in the regulatory functions of inflammatory processes. In this review, we describe the recent advances in knowledge regarding the manner in which caspase-8 modulates the inflammatory responses concerning inflammasome activation, cell death, and cytokine induction.

Keywords: apoptosis; caspase-8; inflammasome; inflammation; necroptosis; pyroptosis.

Figure 1

(a) Schematic showing the important residues involved in activation of human caspase-8. Procaspase-8 (p55/p53) is an inactive precursor composed of two death effector domains (DEDs), a large subunit (p18) and a small subunit (p10). The maturation of caspase-8 is derived by its auto-processing between p18 and p10 and subsequently between p18 and the pro-domain [3,4]. The mature caspase-8 consists of two large subunits and two small subunits. (b) Substrates of caspase-8 and targeted cleavage sites. Caspase-8 is involved in inflammation processes in a variety of ways: immune silent apoptosis induction through the cleavage of caspase-3 and bid [6,7,8]; inflammation induction by processing IL-1β and gasdermin D (GSDMD) [9,10]; inhibition of inflammatory cell death (necroptosis) by targeting Receptor-interacting protein kinase (RIPK)1, RIPK3 and cylindromatosis (CYLD) [11,12,13,14]; NF-κB activation through cellular Fas-associated protein with death domain (FADD)-like IL-1β-converting enzyme (FLICE)-inhibitory protein (cFLIP) cleavage fragments [15].

Figure 2

Caspase-8 contributes to the inhibition of inflammation through the induction of apoptosis, inhibition of necroptosis, and limiting of proinflammatory processes. Upon stimulation of death receptors, such as TNFR1, caspase-8 forms a complex with FADD, RIPK1, and Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD) and is activated. The activated caspase-8 induces apoptotic cell death through the processing of effector caspases, such as caspase-3, -6, and -7. Caspase-8 inhibits necroptosis, a cell death mode that leads to inflammation by targeting the pro-necroptotic molecules RIPK1, RIPK3, and CYLD. In addition, caspase-8 is required for the inhibition of Toll-like receptor (TLR)-induced, MLKL-mediated inflammasome activation. The caspase-8 cleavage of RIPK1 also contributes to limiting proinflammatory cytokine production mediated by NF-κB or IRF3 in response to TNF or Sendai virus. Blue arrows indicate activation and red blunt arrows represent inbibition. The blue dot arrows indicate the release of molecules.

Figure 3

Caspase-8 promotes inflammation through IL-1β and GSDMD processing, activation of the inflammasome, and NF-κB activation. Caspase-8 can directly cleave IL-1β upon stimulation of FAS/Dr3, Dectin-1, and TLR with cellular stress conditions, such as chemotherapeutic drugs, ER stress, and cIAP inhibition. Caspase-8 mediates pyroptosis by direct processing of GSDMD in response to Yersinia infection or by induction of inflammasome activation through caspase-1 activation by its scaffolding function. Fas cell surface death receptor (FAS) and death receptor 3 (DR3) signal FADD-caspase-8 to process IL-1β and dectin-1 ligation induces IL-1β processing through caspase-8 assisted by Bcl-10, MALT-1, and ASC. Caspase-8 contributes to T-cell receptor (TCR)- or TLR-induced NF-κB activation, production of proinflammatory cytokines, and priming of the inflammasome.