Caspase‐1‐induced pyroptotic cell death

Abstract

Summary Programmed cell death is a necessary part of development and tissue homeostasis enabling the removal of unwanted cells. In the setting of infectious disease, cells that have been commandeered by microbial pathogens become detrimental to the host. When macrophages and dendritic cells are compromised in this way, they can be lysed by pyroptosis, a cell death mechanism that is distinct from apoptosis and oncosis/necrosis. Pyroptosis is triggered by Caspase-1 after its activation by various inflammasomes, and results in lysis of the affected cell. Both pyroptosis and apoptosis are programmed cell death mechanisms, but are dependent on different caspases, unlike oncosis. Similar to oncosis, and unlike apoptosis, pyroptosis results in cellular lysis and release of the cytosolic contents to the extracellular space. This event is predicted to be inherently inflammatory, and additionally coincides with IL-1β and IL-18 secretion. We discuss the role of distinct inflammasomes, including NLRC4, NLRP3 and AIM2, as well as the role of the ASC focus in Caspase-1 signaling. We further review the importance of pyroptosis in vivo as a potent mechanism to clear intracellular pathogens.

Pyroptotic Neuronal Cell Death Mediated by the AIM2 Inflammasome

“…It is proposed that the ASC focus is more important for activation of cytokines, while diffuse ASC is critical for execution of pyroptosis. 34 Diffuse ASC staining of neurons undergoing pyroptosis observed in our studies supports this conclusion.…”

Old, new and emerging functions of caspases

“…FADD, FAS-associated death domain; TNFR1, TNF receptor 1; TRADD, TNF receptor-associated death domain; cIAP1, cellular inhibitor of apoptosis protein 1; RIP1, receptor-interacting protein 1; MLKL, mixed lineage kinase domain-like; cFLIP, cellular FLICE-like inhibitory proteins; MOMP, mitochondrial outer membrane permeabilization caspases, resulting in plasma membrane pore formation allowing water influx, cell swelling and osmotic lysis, followed by release of proinflammatory intracellular contents. 32,34 This demarcates it clearly from apoptosis where no loss of membrane integrity is observed. At the same time cytokines are secreted either through the newly formed plasma membrane pores or through microvesicles-or lysosomemediated exocytosis.…”

“…36 Chromosomal DNA cleavage and nuclear condensation occurs in pyroptosis but in the absence of oligonucleosomal DNA fragmentation or cleavage of typical caspase substrates such as PARP and ICAD that are characteristic of apoptosis. 34,37 Autophagy. Cross talk between autophagy and apoptosis is well established.…”

“…34,56 Caspase-1 is the prototypical member of the inflammatory caspase family, while; the functions of caspase-4 and -5 are not well defined (caspase-5 is absent in mice and mouse caspase-11 is a paralogue of human caspase-4). Caspase-11 has been suggested to be an upstream activator of caspase-1 but unlike caspase-1, caspase-11 expression is induced by LPS at the transcriptional level.…”

Les inflammasomes

“…Outre sa fonction activatrice d'interleukines pro-inflammatoires, la caspase-1 est capable d'engager la cellule dans un processus de mort inflammatoire programmée, appelée pyroptose, restreinte à certains types cellulaires (dont les macrophages, les cellules dendritiques, ou les neurones) [4,32]. La pyroptose est déclenchée en réponse à de nombreux stimulus, qu'il s'agisse de PAMP ou de DAMP.…”