No longer married to inflammasome signaling: the diverse interacting pathways leading to pyroptotic cell death

Abstract

For over 15 years the lytic cell death termed pyroptosis was defined by its dependency on the inflammatory caspase, caspase-1, which, upon pathogen sensing, is activated by innate immune cytoplasmic protein complexes known as inflammasomes. However, this definition of pyroptosis changed when the pore-forming protein gasdermin D (GSDMD) was identified as the caspase-1 (and caspase-11) substrate required to mediate pyroptotic cell death. Consequently, pyroptosis has been redefined as a gasdermin-dependent cell death. Studies now show that, upon liberation of the N-terminal domain, five gasdermin family members, GSDMA, GSDMB, GSDMC, GSDMD and GSDME can all form plasma membrane pores to induce pyroptosis. Here, we review recent research into the diverse stimuli and cell death signaling pathways involved in the activation of gasdermins; death and toll-like receptor triggered caspase-8 activation of GSDMD or GSMDC, apoptotic caspase-3 activation of GSDME, perforin-granzyme A activation of GSDMB, and bacterial protease activation of GSDMA. We highlight findings that have begun to unravel the physiological situations and disease states that result from gasdermin signaling downstream of inflammasome activation, death receptor and mitochondrial apoptosis, and necroptosis. This new era in cell death research therefore holds significant promise in identifying how distinct, yet often networked, pyroptotic cell death pathways might be manipulated for therapeutic benefit to treat a range of malignant conditions associated with inflammation, infection and cancer.

An anti-mesothelin targeting antibody drug conjugate induces pyroptosis and ignites antitumor immunity in mouse models of cancer

“…It is increasingly acknowledged that the relationship between pyroptosis and apoptosis is complex, and that both pathway intermediates such as caspase-3 and effectors such as GSDME can variously be employed to determine the kind of programmed cell death. 57 Here, however, it is important to recognize that treatments that induce tumor cell pyroptosis may sidestep the resistance of many cancers to treatment-induced apoptosis. Data presented herein demonstrate that mesoADC treatment of mice with GSDME-expressing tumors results in antitumor effects mediated both by tubulysin-induced pyroptotic tumor cell death and tubulysin-induced DC maturation together with the recruitment of pyroptosis-inducing cytotoxic T cells to the tumor.…”

The escape of Candida albicans from macrophages is enabled by the fungal toxin candidalysin and two host cell death pathways

“…However, C. albicans can overcome Nlrp3 inactivation, possibly by utilizing MET formation (i.e., ETosis). How METs form in the absence of active Nlrp3 inflammasome has yet to be defined, but it may involve alternate cell death proteins, such as caspase-8 or Gasdermin E (Weir and Vince, 2022). Candidalysin could also be involved in the mechanism because the ece1D/D strain displayed reduced escape from (A) Release of IL-1b quantified by ELISA from supernatants of BMDMs challenged with C. albicans WT, ece1D/D, and ece1D/D + ECE1 strains.…”

Cell death and inflammation during obesity: “Know my methods, WAT(son)”

“…There are, however, other sensors that can form a variety of inflammasome platforms. Whereas the NLPR3 senses DAMPs, the NLRP1 sense viral particles and dsRNA, NLRC4 senses pathogen associated molecular patterns (PAMPs) and AIM2 senses dsDNA [ 46 ]. Inflammasome formation results in the activation of Caspase-1 that cleaves pro-IL1β and Gasdermin D. Activated Gasdermin D oligomerises in the membrane and forms pores from which mature IL1β, among other cytokines, is released (Fig.…”