Caspase-1-induced pyroptotic cell death

Abstract

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 coincides with interleukin-1β (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.

Figure 1. Role of ASC in cytokine processing and pyroptosis

All known inflammasomes recruit ASC, resulting in the formation of the ASC focus (microscopic image to left showing ASC focus after L. monocytogenes infection in a macrophage). Caspase-1 is processed in the ASC focus and cleaves pro-IL-1β and pro-IL-18 to their mature, secreted forms. CARD-containing inflammasomes, such as NLRC4, also bind Caspase-1 independent of ASC, and this complex does not require Caspase-1 processing, and triggers pyroptosis. Pyrin-containing inflammasomes, such as AIM2 and NLRP3, trigger pyroptosis through ASC.

Figure 2. Pyroptosis promotes clearance of intracellular microbes

Schematic of the role of pyroptosis in clearing intracellular pathogens. Numerous pathogens have the ability to replicate within macrophages (upper panel), eventually being released in greater numbers. Although neutrophils have the capacity to kill many macrophage tropic pathogens, the intracellular niche within the macrophage compartment permits these pathogens to continue a pathogenic replicative cycle. Intracellular pathogens that are detected by an inflammasome (lower panel) activate Caspase-1, resulting in pyroptosis. This releases the bacteria from the macrophage prior to replication, effectively short-circuiting the pathogenic replicative cycle. Released bacteria are thereby exposed to additional clearance mechanisms, including phagocytosis by neutrophils.