Pyroptosis, an inflammatory programmed cell death process, was first discovered in the process of cell infection, which later found as a downstream inflammatory body (including Caspase-1) and other caspases, widely involved in the inflammatory process of cell death in a variety of diseases. Pyroptosis and other programmed cell death complement each other, connect and transform each other, constitute a complex system of programmed cell death.
Key words: Pyroptosis, GSDMD, immunity.
Pyroptosis is a form of cell death that is critical for immunity. It can be induced by the canonical caspase-1 inflammasomes or by activation of caspase-4, -5 and -11 by cytosolic lipopolysaccharide1–3 that can also result in a potent and sometimes pathological inflammatory response. It is a novel type of programmed cell death, which is closely related with the pathogenesis of myelodysplastic syndromes (MDS). The caspases cleave gasdermin D (GSDMD) in its middle linker to release autoinhibition on its gasdermin-N domain, which executes pyroptosis via its pore-forming activity4–9. GSDMD belongs to a gasdermin family that shares the pore-forming domain.
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Pyroptosis is a form of cell death important in defenses against pathogens. The recent studies showed that all of S100A9/TLR4, S100A9/CD33 and Nox/ROS signaling pathways can activate oxygen-sensitivity NLRP3 inflammasome. It induces the pyroptosis of hematopoeitic stem cells (HSC) / hematopeitic pregenitor cells (HPC). Further studies on the role and molecular mechanism of pyroptosis in the pathogenesis of MDS will provide the potential opportunity for the diagnosis and treatment of it.
Pattern recognition receptors (PRRs) recognize pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) released by organisms when cells are infected by external microorganisms, such as bacteria. Thus, the innate immune response is quickly activated to prevent the invasion of pathogenic microorganisms. Pattern recognition receptors are generally expressed in macrophages, monocytes, dendritic cells, neutrophils, epithelial cells and some cells in the adaptive immune system.
Pyroptosis is a highly inflammatory form of programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. During pyroptosis, GSDMD (gasdermin D), a critical protein that is result in rapid cell death which immune cells recognize foreign danger signals within themselves, release pro-inflammatory cytokines, swell, burst and die.
A wide variety of pathogenic microorganisms have been demonstrated to cause eukaryotic cell death, pathogen-induced host cell death has been characterized as apoptosis in many of these systems. It is increasingly being recognized that cell death with some of the features of apoptosis may result from a variety of molecular pathways and that experimental techniques used to identify cell death often do not distinguish among these mechanisms.
Macrophages mediate crucial innate immune responses via caspase-1-dependent processing and secretion of interleukin 1β (IL-1β) and IL-18. This clearance was independent of IL-1β and IL-18. Instead, caspase-1-induced pyroptotic cell death released bacteria from macrophages and exposed the bacteria to uptake and killing by reactive oxygen species in neutrophils. Similarly, activation of caspase-1 cleared unmanipulated Legionella pneumophila and Burkholderia thailandensis by cytokine-independent mechanisms. This demonstrates that activation of caspase-1 clears intracellular bacteria in vivo independently of IL-1β and IL-18 and establishes pyroptosis as an efficient mechanism of bacterial clearance by the innate immune system.
Eukaryotic cells can initiate several distinct programmes of self-destruction, and the nature of the cell death process (non-inflammatory or proinflammatory) instructs responses of neighbouring cells, which in turn dictates important systemic physiological outcomes. Pyroptosis, or caspase 1-dependent cell death, is inherently inflammatory, is triggered by various pathological stimuli, such as stroke, heart attack or cancer, and is crucial for controlling microbial infections. Pathogens have evolved mechanisms to inhibit pyroptosis, enhancing their ability to persist and cause disease. Ultimately, there is a competition between host and pathogen to regulate pyroptosis, and the outcome dictates life or death of the host.
Pyroptosis corresponds to an intensely inflammatory form of programmed cell death in which cytoplasmic contents and pro-inflammatory cytokines, including IL-1β, are released. The cycle can be broken by caspase 1 inhibitors shown to be safe in humans, raising the possibility of a new class of ‘anti-AIDS’ therapeutics targeting the host rather than the virus.
Pyroptosis, as an inflammatory programmed cell death, has attracted considerable attention in various disease models and is believed to be a hot spot for fund applications in recent years. At present, many reports have shown that Pyroptosis is involved in the inflammatory process of many diseases, such as tumor, infectious disease, cardiovascular disease, neuroinflammation. Many researchers who have paid close attention to the signal pathway of inflammatory bodies in the past may naturally extend to the study of the mechanism of cell burnout. A new upsurge of cell death research.
