Mechanism and Features of Cell Pyroptosis

The nature of the cell death process (non-inflammatory or pro-inflammatory) dictates the response of neighboring cells, which in turn determines important systemic physiological outcomes. Pyroptosis, or caspase 1-dependent cell death, is inflammatory in nature, triggered by various pathological stimuli such as stroke, heart attack, or cancer, and is critical for the control of microbial infections. Pathogens have evolved mechanisms to suppress pyroptosis, enhancing their ability to persist and cause disease. 

Apoptosis is perhaps the most widely recognized cell death program and is mechanistically defined by the requirement for specific cysteine-dependent aspartate-specific proteases, or caspases, that generate orchestrated cell breakdown. Apoptotic caspases cleave cellular substrates, leading to features of apoptosis, including cytoplasmic and nuclear condensation, DNA cleavage, and maintenance of an intact plasma membrane.

Pyroptosis is morphologically and mechanistically distinct from other forms of cell death. Caspase 1 dependence is a defining feature of pyroptosis, an enzyme that mediates the cell death process. Caspase 1 is not involved in apoptosis, and caspase 1-deficient mice have no apoptosis defects and develop normally. Apoptotic caspases, including caspases, caspases, and caspases not involved in pyroptosis, and substrates of apoptotic caspases, including poly(ADP -ribose) polymerase and inhibitor of caspase-activated DNase ( ICAD ), proteolysis is not performed during pyroptosis. In addition, loss of mitochondrial integrity and cytochrome c that can activate apoptotic caspases The release of does not occur during pyroptosis.

Pyroptosis is characterized by rapid rupture of the plasma membrane and release of proinflammatory intracellular contents. This is in stark contrast to the packaging of cellular contents and the non-inflammatory phagocytic uptake of membrane-bound apoptotic bodies that characterize apoptosis. Cell lysis during pyroptosis is caused by a caspase 1-mediated process. Salmonella infection or B. anthracis lethal toxin treatment produces plasma membrane pores with a functional diameter of 1.1–2.4 nm and pore formation is a host cell-mediated process that is dependent on caspase 1 activity.

Caspase 1-dependent membrane pores dissipate the cellular ion gradient, generating a net increase in osmotic pressure, water influx, cell swelling, and ultimately osmotic lysis and release of inflammatory intracellular contents. In fact, cells that die by pyroptosis experience a measurable increase in size. In support of this mechanism, the cytoprotectant glycine nonspecifically blocks ion flux in damaged eukaryotic cells, thereby preventing swelling and lysis during pyroptosis.

Disruption of the actin cytoskeleton has also been observed in pyroptosis, but the mechanism and importance of this disruption remain unclear. Caspase 1-dependent degradation of inhibitor of apoptosis protein (cIAP) also accompanies pyroptosis, although the exact mechanism of cIAP degradation is unknown. Caspase 1 cleaves and inactivates metabolic enzymes during pyroptosis, and the identification of additional proteolytic targets of caspase 1 may provide insights into the mechanisms of pyroptosis and novel features of this form of cell death.

Pyroptosis prevents infection and induces pathological inflammation. Although caspase 1 activity and pyroptosis can serve as a protective host response to infectious disease, excessive or inappropriate caspase 1 activation and pyroptosis can be detrimental. Mutations in NLR proteins can lead to inappropriate activation of caspase 1, which is associated with inherited autoinflammatory syndromes. Furthermore, caspase 1 is involved in the pathogenesis of several diseases, including myocardial infarction, cerebral ischemia, inflammatory bowel disease, neurodegenerative disease, and endotoxic shock, each characterized by inflammation and cell death.

Caspase 1 deficiency or pharmacological inhibition prevents the inflammation, cell death, and organ dysfunction associated with these diseases, making caspase 1 an attractive therapeutic target. Neutralization of the cytokine targets IL-1β and IL-18 did not mimic the protective effects of caspase 1 deficiency in sepsis and renal failure, suggesting that caspase 1 plays a role in disease in addition to cytokine processing have other effects.