Great balls of fire: activation and signalling of inflammatory caspases

Abstract

Innate immune responses are tightly regulated by various pathways to control infections and maintain homeostasis. One of these pathways, the inflammasome pathway, activates a family of cysteine proteases called inflammatory caspases. They orchestrate an immune response by cleaving specific cellular substrates. Canonical inflammasomes activate caspase-1, whereas non-canonical inflammasomes activate caspase-4 and -5 in humans and caspase-11 in mice. Caspases are highly specific enzymes that select their substrates through diverse mechanisms. During inflammation, caspase activity is responsible for the secretion of inflammatory cytokines and the execution of a form of lytic and inflammatory cell death called pyroptosis. This review aims to bring together our current knowledge of the biochemical processes behind inflammatory caspase activation, substrate specificity, and substrate signalling.

Pyroptosis-Mediated Periodontal Disease

“…Innate immune responses are tightly regulated by various pathways to control infections and maintain homeostasis [ 29 ]. Hence, the innate immune system is strongly related to inflammation, which is a host tissue response to an assault commonly triggered by microorganisms or other stimuli such as chemicals, radiation, or trauma, and their released products (i.e., metabolites, endotoxins).…”

“…The inflammasome is one of the pathways of the innate immune system, which activates a family of cysteine proteases called inflammatory caspases. These caspases control the immune response by cleaving specific cellular substrates [ 9 , 29 , 34 ]. Inflammasomes often require activation by danger signals.…”

“…Caspase-1 is pivotal for pyroptosis. It was originally termed “interleukin converting enzyme” for its well-established role in the cleavage of IL-1β and IL-18 [ 29 ]. Upon sensing PAMPs and DAMPs, innate immune cells form inflammasomes that recruit and activate caspase-1, known as the canonical inflammasome pathway.…”

“…Other inflammatory caspases, such as caspase-4 and -5, directly bind bacterial LPS, triggering pyroptosis, which is the non-canonical inflammasome pathway. However, the non-canonical pathway ultimately leads to canonical inflammasome engagement through caspase-1 activation ( Figure 1 ) [ 29 ]. By including specific caspase-1 inhibitors––Ac-YVAD-CHO, for instance, it is possible to discriminate caspase-1 activity from the activity of other caspases, and pyroptosis from other types of cell death [ 72 ].…”

“…Such cytokines recruit more inflammatory cells to trigger the inflammatory cascade. Additionally, GSDMD pores generate potassium efflux that allow caspase-1 activation through NLRP3 inflammasome ( Figure 1 ) [ 1 , 9 , 29 , 47 ]. Thus, GSDMD is a central effector of pyroptosis that has different roles inside the cells, while the most remarkable activity is the formation of pores in the cell membrane, which allow the release of interleukins to the extracellular matrix, then provoking an intense inflammatory reaction.…”