By Sarah Choi
Cell death and its regulation are integral to human development and function. Indeed, the role of cell death in disease progression further suggests malfunction can have fatal consequences. Over the years, studies on the role of cell death in diseases and the pathways involved has inspired therapeutics that harness the power of cell death in favour of healthy cells and against aberrant cells. In particular, the role of pyroptosis in normal development and its implication in a wide range of diseases suggests a deeper understanding of this process can benefit patients.
Pyroptosis is an inflammatory and lytic form of programmed cell death. It involves pore formation on the plasma membrane driven by activation of the gasdermin family of proteins, as well as inflammasome- and caspase-directed release of interleukin-1β (IL-1β) and interleukin-18 (IL-18). Overall, this culminates in cell swelling and membrane rupture, fostering an inflammatory microenvironment that can be harnessed against disease progression.
One of the main roles of pyroptosis in health is as the body’s antimicrobial immune response. Studies in knockout mice have highlighted the importance of caspase-1 and caspase-11, enzymes that mediate pyroptosis, in combating infections (Man, Karki and Kanneganti, 2017). Upon infection by bacteria, viruses, fungi, or protozoan pathogens, activation of caspases by both host and microbial factors leads to inflammatory pyroptosis. The innate immune system uses this to eliminate pathogens by pyroptotic cell death, thus counteracting infectious diseases. Pathogens therefore compete against host cells to inhibit pyroptosis using virulence factors, such that they can increase their own chances of survival. In response, the host can upregulate sensor proteins, activate macrophages, and increase utilization of pyroptotic cell death by macrophages (Bergsbaken, Fink and Cookson, 2009). However, while inflammatory signals recruit immune cells and enhance the innate and adaptive immune response, the pro-inflammatory cascade of events involved in pyroptosis can also contribute to autoimmune and inflammatory diseases.
Evasion of cell death and immune destruction are hallmarks of cancer. The development of cancer therapies therefore includes endeavours to reverse these characteristics. Recently, pyroptosis as a form of cancer cell death has gained attention. Natural killer cells and cytotoxic T cells use the granzyme-mediated pathway of pyroptosis to promote antitumor immunity and eliminate cancer cells. Research has shown that specific granzymes cleave and activate different members of the gasdermin family, triggering pyroptosis and inflammation. By expressing gasdermin in tumor cells, pyroptosis can be activated to enhance immunotherapies that have been less effective, especially against immunologically “cold” tumors not infiltrated by immune cells (Zhang, Zhang and Lieberman, 2021).
Gasdermin expression can also amplify the cytotoxic effects of chemotherapy, and various molecules and existing drugs can induce pyroptosis in tumors. It has been shown that chemotherapy and target therapy drugs can induce pyroptosis via the activation of gasdermin E (GSDME) (the caspase-3 mediated pathway) instead of the more well-known gasdermin D (GSDMD). In fact, it seems GSDME is a tumor suppressor required for pyroptosis in cancer cells – and therefore silenced in many cancers. For example, in gastric cancer, the expression and cleavage of GSDME allows chemotherapy-induced apoptosis to switch to pyroptosis (Wang et al., 2018). However, this was only shown in vitro, with one specific chemotherapeutic drug. Further investigations into the mechanisms and regulation of pyroptosis in cancer cells are undoubtedly needed. This can aid the development of therapies that promote or activate pyroptosis in cancer cells specifically. Further goals include reducing pyroptosis of hematopoietic and immune cells and alleviating the toxic side effects of drugs.
Similar to the unwanted growth of tumor cells, the established role of pyroptosis in endometriosis and gynaecological cancers has inspired development of treatments that induce pyroptosis of endometrial and tumour cells. This being said, treatments for other gynaecological diseases usually target inflammasomes and gasdermins to inhibit pyroptosis. During embryonic development, pyroptosis is fundamental for successful implantation, placentation, and neurodevelopment. However, excessive activation of inflammasome-dependent pyroptosis is deleterious for both the mother and the foetus. Furthermore, excessive pyroptosis causes various obstetrical and gynaecological diseases, including polycystic ovary syndrome and preeclampsia (Yu and Li, 2021). This is similar to the aforementioned inflammatory diseases, in which pyroptosis becomes detrimental for the body. The role of pyroptosis in these diseases is yet to be completely elucidated, and further understanding of the roles of upstream and downstream molecules in the pyroptosis signalling pathway can illuminate the therapeutic potential of targeting particular molecules.
Additionally, recent studies have suggested that pyroptosis contributes to the pathogenesis of neurological diseases, including Alzheimer’s disease, multiple sclerosis, Parkinson’s disease, and stroke. Disruption of homeostasis and other aberrant signals present in these diseases (such as abnormal protein aggregation) induce pyroptosis in multiple cell types of the central nervous system. This results in neuroinflammation, neurodegeneration, and glial cell death (Zhao and Xie, 2014; McKenzie, Dixit and Power, 2020). Inhibiting pyroptosis could therefore alleviate symptoms, and therapeutic strategies targeting pyroptosis in neurological injury and disease have indeed shown promise. For example, fenamate non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to effectively inhibit the NLRP3 inflammasome, exhibiting neuroprotective effects in mouse models of Alzheimer’s disease (Daniels et al., 2016). A recent study on Parkinson’s disease that used behavioural tests in mice also found salidroside to be effective in reducing NLRP3, IL-1β and IL-18. This resulted in direct and indirect inhibition of the pyroptosis induced in mice (Zhang et al., 2020). Salidroside could therefore potentially be administered to alleviate symptoms in Parkinson’s disease and prevent neurodegeneration.
Pyroptosis plays a role in many other diseases, for example affecting the pathogenesis and clinical outcomes of cardiovascular diseases and COVID-19. Further knowledge of the specific roles of molecules involved in pyroptosis in health and disease can advance efforts to develop treatments. Rigorous research is also needed to enhance understanding of the different pathways of pyroptosis observed in various cell types. This could then accelerate the realization of disease treatment options that can trigger or suppress pyroptosis as needed in different cells.
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