The role of caspase-8 in inflammatory signalling and pyroptotic cell death

• Published in: Seminars in immunology 2023-11, Vol.70, p.101832-101832, Article 101832
• Main Authors: Pang, Jiyi, Vince, James E
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - physiology; Caspase 1 - metabolism; Caspase 8 - metabolism; Caspases - metabolism; Humans; Inflammasomes - metabolism; Mice; Pyroptosis - physiology
• ISSN: 1044-5323; 1096-3618
• DOI: 10.1016/j.smim.2023.101832

The programmed cell death machinery exhibits surprising flexibility, capable of crosstalk and non-apoptotic roles. Much of this complexity arises from the diverse functions of caspase-8, a cysteine-aspartic acid protease typically associated with activating caspase-3 and - 7 to induce apoptosis. However, recent research has revealed that caspase-8 also plays a role in regulating the lytic gasdermin cell death machinery, contributing to pyroptosis and immune responses in contexts such as infection, autoinflammation, and T-cell signalling. In mice, loss of caspase-8 results in embryonic lethality from unrestrained necroptotic killing, while in humans caspase-8 deficiency can lead to an autoimmune lymphoproliferative syndrome, immunodeficiency, inflammatory bowel disease or, when it can't cleave its substrate RIPK1, early onset periodic fevers. This review focuses on non-canonical caspase-8 signalling that drives immune responses, including its regulation of inflammatory gene transcription, activation within inflammasome complexes, and roles in pyroptotic cell death. Ultimately, a deeper understanding of caspase-8 function will aid in determining whether, and when, targeting caspase-8 pathways could be therapeutically beneficial in human diseases.