Abstract
Pyroptosis is a proinflammatory form of cell death, mediated by membrane pore-forming proteins called gasdermins. Gasdermin pores allow the release of the pro-inflammatory cytokines IL-1β and IL-18 and cause cell swelling and cell lysis leading to release of other intracellular proteins that act as alarmins to perpetuate inflammation. The best characterized, gasdermin D, forms pores via its N-terminal domain, generated after the cleavage of full length gasdermin D by caspase-1 or -11 (caspase-4/5 in humans) typically upon sensing of intracellular pathogens. Thus, gasdermins were originally thought to largely contribute to pathogen-induced inflammation. We now know that gasdermin family members can also be cleaved by other proteases, such as caspase-3, caspase-8 and granzymes, and that they contribute to sterile inflammation as well as inflammation in autoinflammatory diseases or during cancer immunotherapy. Here we briefly review how and when gasdermin pores are formed, and then focus on emerging endogenous mechanisms and therapeutic approaches that could be used to control pore formation, pyroptosis and downstream inflammation.
Highlights
GASDERMIN-MEDIATED CELL DEATH AS A DRIVER OF INFLAMMATIONApoptosis is traditionally viewed as a non-inflammatory form of caspase-dependent programmed cell death [1]
Caspase-mediated inactivation of innate immune signaling molecules and the preservation of membrane integrity ensures that apoptotic cells remain immunologically silent [2]
GSDMB and GSMDE induce the death of tumor cells by pyroptosis, resulting in low-grade local inflammation that is essential for successful clearance of tumors by myeloid cells [21, 22]
Summary
Apoptosis is traditionally viewed as a non-inflammatory form of caspase-dependent programmed cell death [1]. During infection, gasdermin D (GSDMD) is cleaved by caspase-1, Control of Gasdermin-Mediated Pyroptosis caspase-8 and caspase-11 (caspase 4/5 in humans), to release its membrane pore-forming fragment and induce pyroptotic death of infected cells [4,5,6,7,8,9,10]. Several chemotherapy drugs that were designed to induce non-inflammatory apoptosis of tumors, end up causing systemic pathology, by activating the apoptotic caspase-3, which can cleave GSDME into its pore-forming fragment These systemic drugs induce pyroptosis in GSDME-positive tumors, and in other GSDMEexpressing healthy cells, leading to wide-spread inflammation, tissue damage and weight loss [24].
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