Pyroptosis in development, inflammation and disease

Abstract

In the early 2000s, caspase-1, an important molecule that has been shown to be involved in the regulation of inflammation, cell survival and diseases, was given a new function: regulating a new mode of cell death that was later defined as pyroptosis. Since then, the inflammasome, the inflammatory caspases (caspase-4/5/11) and their substrate gasdermins (gasdermin A, B, C, D, E and DFNB59) has also been reported to be involved in the pyroptotic pathway, and this pathway is closely related to the development of various diseases. In addition, important apoptotic effectors caspase-3/8 and granzymes have also been reported to b involved in the induction of pyroptosis. In our article, we summarize findings that help define the roles of inflammasomes, inflammatory caspases, gasdermins, and other mediators of pyroptosis, and how they determine cell fate and regulate disease progression.

Keywords: caspase-1; disease; gasdermins; inflammation; pyroptosis.

Figure 1

Timeline of the key discoveries about the pyroptosis.

Figure 2

Inflammasomes in the canonical and non-canonical pyroptotic pathway. In the canonical pathway, danger-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs) activate their respective inflammasome sensors, including NLRP1, NLRP3, NLRC4, AIM2, or Pyrin. B. Anthrax toxins, Toxoplasma, ATP, etc. activate the NLRP1 inflammasome, and NLRP1 recruits pro-caspase-1 via ASC or via CARD-CARD interaction. Multiple DAMPs and PAMPs activate the NLRP3 inflammasome, which subsequently recruits ASCs and pro-caspase-1. NLRC4 senses bacterial flagellin and T3SS/T4SS components and activates caspase-1 in an ASC-dependent or ASC-independent manner. The AIM2 inflammasome assembles when AIM2 senses host- or pathogen-derived dsDNA; the pyrin inflammasome is activated by Rho-inactivating toxins, and both AIM2 and pyrin activate caspase-1 in an ASC-dependent manner. Activated caspase-1 induces proteolytic cleavage of GSDMD to generate N-GSDMD, which then forms the GSDMD-N pore and induces pyroptosis. Activated caspase-1 also induces proteolytic maturation of IL-1β and IL-18 to their active forms, which are secreted through the GSDMD-N pore. In the non-canonical pathway, LPS from Gram-negative bacteria are recognized by caspase-4 or caspase-5 in human cells or caspase-11 in mouse cells. These activated inflammatory caspases directly cleave GSDMD and form GSDMD-N pores to trigger pyroptosis. The GSDMD-N-terminal fragment also activates the NLRP3 inflammasome and induces caspase-1-dependent maturation of IL-1β and IL-18. CARD, caspase recruitment domain; LRRs, leucine-rich repeats; BD, nucleotide-binding and oligomerization domain; PYD, pyrin domain; N FIIND, a functional-to-find domain; HIN-200, hematopoietic interferon-inducible nuclear protein 200; CC, coiled-coil; B-box, B-box-type zinc finger; AIM2, absent in melanoma 2; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; GSDMD, gasdermin D; LPS, lipopolysaccharide.