Pyroptosis: Mechanisms mediating cell death and pro-inflammatory cytokine release

By Victoria Osinski

Pyroptosis is an inflammatory form of programmed cell death characterized by the release of pro-inflammatory cytokines IL-1β and IL-18.^1,10 It is a process distinct from apoptosis and necrosis (Table 1) and has been observed in the setting of multiple diseases including, but not limited to, microbial infection¹⁰, atherosclerosis and other cardiovascular diseases⁶, sepsis⁴, and liver disease⁵. Of note, cell death is defined as “programmed” when a cell relies on its own intrinsic cellular signaling to initiate the process.² The canonical form of pyroptosis is defined as caspase-1-dependent, though multiple studies have identified caspase-1-independent pyroptosis pathways. Pyroptosis and its molecular mechanisms are a growing area of interest because they serve as potential novel therapeutic targets for a number of diseases.⁹

Table 1: Differences between apoptosis, necrosis, and pyroptosis.

Based on findings summarized in References 2, 3, 10

Caspase-1-dependent pyroptosis:

Caspase 1 is induced by the pattern recognition receptors Nucleotide-binding oligomerization domain and leucine-rich repeat receptors (NLRs), including NLRP3, NLRP1b, and NLRC4/CARD12.¹ These receptors can recognize and respond to PAMPs and DAMPs originating from bacterial, viral, and host cell components. Following NLR-Caspase 1 activation, the inflammasome is formed. The inflammasome is a multi-protein structure formed by sensors (such as NLRP3), inflammatory caspases, and an inflammasome adaptor protein such as apoptosis-associated speck-like protein containing a carboxy-terminal CARD (ASC) (Table 2).^8,9,10

In addition to forming the inflammasome, inflammatory Caspases-1, -4/5, and -11 also activate Gasdermin D, which forms pores in the plasma membrane to release pro-inflammatory cytokines.^7,10 This component of pyroptosis, the active release of pro-inflammatory cytokines, is what make it particularly unique relative to other forms of cell death. Pro-inflammatory cytokines IL-1β and IL-18 are first translated into non-active forms, which are then cleaved and activated by Caspase-1.^3,7,10 These cytokines can then be released via Gasdermin D-formed pores.

Caspase-1-independent pyroptosis:

Gasdermin D can also be activated by Caspase-4,-5, and -11 in a Caspase-1-independent form of pyroptosis. Though, it should be noted that activation of pro-inflammatory IL-1β and IL-18 still rely on Caspase-1 activity in this context.¹⁰ Caspase-3 has also been shown to activate Gasdermin E to form a pore for release of DAMPs and cytokines.³

New information concerning the mechanisms driving pyroptosis continues to emerge and it is evident that this is a complex problem. These advances in our understanding of pyroptosis also reveal its importance in human health and provide opportunities to identify new therapeutic targets.

Table 2: Inflammasome components

*Not necessary for inflammasome assembly, but can contribute
Based on findings summarized in References 1, 8, 9