がん微小環境研究プログラム

】Pyroptosis was discovered as caspase-1-dependent cell death of macrophages that were infected by intracellular pathogens such as Salmonella Typhimurium.However, pyroptosis has been observed in other cell types including T cells, intestinal epithelial cells and various cancer cell lines.Morphologically, pyroptosis resembles necrosis rather than apoptosis.Because pyroptotic cells release inflammatory cytokines such as IL-1 and IL-18 as well as intracellular inflammatory substances called DAMPs or alarmins, pyroptosis is inevitably inflammatory cell death as opposed to apoptosis that is often described as non-inflammatory cell death.Recent reports revealed that in addition to caspase-1, caspase-4 and 5 in humans and caspase-11 in mice mediates pyroptosis.Furthermore, it was discovered that these caspases (caspase-1, 4, 5, 11) cleaves a common protein substrate, gasdermin D (GSDMD), and the resulted N-terminal fragments of GSDMD form pores in the plasma membrane to induce pyroptosis.Interestingly, while the caspase-4/5/11-mediated pyroptosis is highly dependent on GSDMD, we have found that activation of caspase-1 induces cell death in GSDMD-KO cells.Recently, we demonstrated that this caspase-1-mediated and GSDMD-independent cell death is apoptosis dependent on Bid, caspase-9 and 3, but not on caspase-2, 6, 7 and 8.It was previously reported that cortical neurons cultured under oxygen-glucose deprivation (OGD) conditions exhibit caspase-1-dependent apoptosis accompanied with caspase-3 and Bid cleavage.We found that wild-type cortical neurons express caspase-1 but little GSDMD, and Bid-KO neurons as well as caspase-1-KO ones are resistant to OGD treatment.In addition, wild-type bone marrow-derived mast cells, which express GSDMD at very low levels, exhibit Bid-dependent apoptosis in response to caspase-1 activation by LPS + nigericin stimulation.There results revealed that activated caspase-1 induces Bid-dependent apoptosis in both artificially and naturally GSDMD-deficient cells, although the same elicits GSDMD-dependent pyroptosis in GSDMD-sufficient cells (Nat Commun, 2019).Nevertheless, caspase-1 activation induces reduced and delayed apoptosis in GSDMD/Bid-double KO cells compared to GSDMD-single KO cells.We found that caspase-1-mediated apoptosis in GSDMD/Bid-double KO cells is caspse-7 dependent, indicating multiple back up mechanisms for caspase-1-dependent cell death (Microbiol Immunol, 2019).