Introduction
Programmed cell death is a fundamental process in biology that ensures the proper development, maintenance, and elimination of cells in multicellular organisms. Among the diverse mechanisms of programmed cell death, pyroptosis has emerged as a fascinating and highly inflammatory pathway. Discovered in recent years, pyroptosis involves a series of molecular events that culminate in the explosive death of cells and the release of pro-inflammatory signals.
Pyroptosis is orchestrated by inflammasomes, which are protein complexes that act as sensors of cellular stress, infection, or damage. Upon activation, inflammasomes trigger the activation of caspase-1, leading to the cleavage of gasdermin proteins and the subsequent formation of pores in the cell membrane. This pore formation results in cell swelling, membrane rupture, and the release of pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and interleukin-18 (IL-18).
What Is Pyroptosis?
Research on pyroptosis dates back to 1986 when Friedlander observed cell death and rapid release of cell contents in primary mouse macrophages treated with anthrax lethal toxin. In subsequent years, the discovery of caspase-1 by Cerretti et al. and Thornberry et al. shed light on its role as an inflammatory caspase that processes precursor IL-1β into mature IL-1β. In 1992, Zychlinsky et al. first described pyroptosis, observing it in Shigella flexneri-infected macrophages. Chen et al. later found that invasion plasmid antigen B (ipaB) of Shigella flexneri activated caspase-1 in infected macrophages.
Initially, pyroptosis was considered a form of apoptosis due to some shared characteristics. However, in 2001, D'Souza introduced the term "pyroptosis' ' to specifically describe this pro-inflammatory programmed cell death. The role of the inflammasome in activating inflammatory caspases and processing pro-IL-1β was recognized in 2002.
Further research revealed that pyroptosis could be induced by caspase-1 or caspase-11/4/5, and the cleavage of gasdermin D (GSDMD) leads to the formation of pores in the cell membrane, resulting in cell membrane rupture. Recent studies have highlighted the regulatory role of factors like caspase-3/7, the endosomal sorting complexes required for transport (ESCRT) machinery, and fumarate in GSDMD-mediated pyroptosis.
Additionally, various agents such as chemotherapeutic agents, caspase-8, granzyme B (GzmB), and granzyme A (GzmA) have been implicated in inducing pyroptosis. The involvement of pyroptosis in cancer has gained attention, with potential implications for clinical treatments. Pyroptosis is also closely associated with several diseases, including those affecting the nervous system, infectious diseases, autoimmune diseases, and cardiovascular diseases.
In recent years, advancements in our understanding of pyroptosis have unveiled its role in the antitumor immune response, with nuclear PD-L1 and p-Stat3 playing a promoting role. The relationship between pyroptosis and tumors is actively being explored, offering potential avenues for clinical interventions.
What Are the Molecular Mechanisms of Pyroptosis?
Understanding the molecular mechanisms underlying pyroptosis is crucial for its physiological functions and its implications for human health and disease. The following are the steps involved in pyroptosis.
Inflammasome Activation:
Pyroptosis is initiated by the activation of inflammasomes, which are multiprotein complexes responsible for sensing intracellular danger signals, such as pathogen-associated molecular patterns (PAMPs) or danger associated molecular patterns (DAMPs). Several types of inflammasomes have been identified, including NLRP3, NLRC4, AIM2, and Pyrin. These complexes comprise a sensor protein, an adaptor protein, and pro-caspase-1.
Sensor Protein Activation:
The sensor proteins within the inflammasomes detect specific danger signals and undergo conformational changes, leading to their oligomerization and recruitment of the adaptor protein. For example, NLRP3 senses a variety of stimuli, including microbial products, crystals, and cellular damage, through mechanisms that are still being elucidated.
Adaptor Protein Recruitment:
Upon activation, the sensor proteins recruit the adaptor protein, typically ASC (apoptosis-associated speck-like protein containing a CARD domain). ASC provides a scaffold for assembling the inflammasome complex, bringing the sensor protein in proximity to pro-caspase-1.
Pro-Caspase-1 Activation:
The assembly of the inflammasome complex facilitates the autoproteolytic cleavage and activation of pro-caspase-1. This activation occurs through a proximity-induced mechanism, where the aggregated pro-caspase-1 molecules undergo self-cleavage to generate active caspase-1.
Cleavage of Gasdermin Proteins:
One of the critical targets of caspase-1 in pyroptosis is the gasdermin family of proteins. Caspase-1 cleaves gasdermin-D (GSDMD) at a specific site, resulting in the release of the N-terminal fragment of GSDMD. The N-terminal fragment has two functional domains: the N-terminal pore-forming domain and the C-terminal autoinhibitory domain.
Pore Formation and Membrane Rupture:
The N-terminal fragment of GSDMD inserts into the cell membrane, forming large pores known as gasdermin pores. These pores cause ion imbalances and osmotic swelling and ultimately lead to cell membrane rupture and lysis. The release of intracellular contents, including pro-inflammatory cytokines and damage-associated molecular patterns (DAMPs), contributes to the inflammatory response associated with pyroptosis.
Pro-Inflammatory Cytokine Release:
In addition to cell lysis, pyroptosis is characterized by the release of pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and interleukin-18 (IL-18). Caspase-1 cleaves pro-IL-1β and pro-IL-18 into their active forms, which are then released extracellularly to promote inflammation and immune responses.
What Are the Implications of Pyroptosis in Human Health and Disease?
The following are the implications of pyroptosis in human health and disease -
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Infectious Diseases: Pyroptosis is critical in host defense against microbial infections. It is an important mechanism for eliminating intracellular pathogens like bacteria, viruses, and parasites. Activation of pyroptosis in infected cells leads to the release of pro-inflammatory cytokines, attracting immune cells to the site of infection and aiding in pathogen clearance. However, excessive or dysregulated pyroptosis can contribute to tissue damage and inflammation, as seen in sepsis and certain viral infections.
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Inflammatory Disorders: Dysregulated pyroptosis can contribute to the development and progression of various inflammatory disorders. Excessive or prolonged activation of inflammasomes and pyroptosis can cause chronic inflammation, tissue damage, and organ dysfunction. Disorders like inflammatory bowel disease (IBD), rheumatoid arthritis, and atherosclerosis have been associated with aberrant pyroptosis. Targeting pyroptosis may hold therapeutic potential for mitigating inflammation and attenuating disease progression.
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Neurodegenerative Diseases: Emerging evidence suggests a role for pyroptosis in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Inflammasome activation and pyroptosis in the central nervous system can contribute to neuronal cell death and neuroinflammation, perpetuating disease progression. Inhibition of pyroptosis has been investigated as a potential therapeutic strategy to protect neurons and mitigate neuroinflammatory responses in these disorders.
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Autoimmune Diseases: Pyroptosis has been implicated in various autoimmune diseases. In which the immune system attacks the body's tissues. Abnormal inflamed activation and pyroptosis can release self-antigens, triggering immune responses and contributing to autoimmunity. Inhibition of pyroptosis has shown promise in experimental models of autoimmune diseases, suggesting its therapeutic potential in managing these conditions.
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Cancer: The role of pyroptosis in cancer is complex. In some cases, pyroptosis can act as a tumor-suppressive mechanism by eliminating cancer cells and inducing antitumor immune responses. However, certain tumors can develop mechanisms to evade pyroptosis or exploit it for their benefit. Understanding the intricate interplay between pyroptosis and tumorigenesis is important for developing effective therapeutic strategies targeting this process.
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Therapeutic Potential: Given the involvement of pyroptosis in various diseases, targeting this cell death pathway has emerged as a potential therapeutic strategy. Modulating inflammasome activation, inhibiting key components of the pyroptotic machinery, or manipulating the release of pro-inflammatory cytokines are being explored as potential avenues for intervention. Preclinical studies targeting pyroptosis have shown promising results, although further research is needed to ensure safety and efficacy in clinical settings.
Conclusion
In summary, pyroptosis is a complex process that is important for immune responses, tissue balance, and disease development. Understanding its mechanisms and functions has advanced the knowledge of cellular biology and led to new therapeutic approaches. Further research on pyroptosis regulation will provide insights for preventing and treating diseases.
