Pyroptosis is a form of inflammatory programmed cell death, triggered by various pathological stimuli such as stroke, heart attack, cancer, and microbial infections. Other known types of programmed cell death include apoptosis and necroptosis. Pyroptosis is fundamentally distinct from other cell death pathways by its exclusive dependency on caspase-1 . Because caspase-1 is a principle effector protease within the pyroptotic cell death pathway, it stands to reason that the intracellular detection of activated caspase-1 be a key indicator of a pyroptosis activity.
Pyroptosis promotes the rapid clearance of various bacterial and viral infections by removing intracellular replication niches and by enhancing the host’s defensive response. Cells can use a broad range of intracellular and extracellular mechanisms for detecting different “danger” signals generated or released during infection or injury. These detection mechanisms typically involve pattern-recognition receptors (PRRs) such as Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), and Absent in melanoma 2 (AIM2) like receptors (ALRs), to name a few . PRRs initiate a signalling cascade that leads to activation and production of inflammatory cytokines upon recognition of conserved microbial signatures or danger signals (commonly referred to as pathogen associated molecular patterns or PAMPs, or danger associated molecular patterns or DAMPS, respectively). Recognition of PAMPs, DAMPs, and some foreign toxins can lead to inflammasome activation, which triggers activation of caspase-1, and the initiation of pyroptosis [1, 3]. Cell surface-associated TLRs typically recognize microbial membrane components (such as the lipid A component from LPS, peptidoglycans, mannan, etc.), while intracellular TLRs recognize bacterial and viral nucleic acids, as well as some “self” nucleic acids present during particular disease states . In addition to promoting an immune response, activation of the inflammasome also leads to an increase in pyroptotic cell death. Some examples of pyroptosis include the death of salmonella-infected macrophages  and T helper (Th) cells that die as a result of abortive HIV infection . In addition, pyroptosis is stimulated by non-infectious stimuli, including host factors produced during myocardial infarction .
Characteristic Features of Pyroptosis Cell Death Pathway
Lysis Through Cell Swelling
Caspase-1-regulated cellular membrane pores dissipate cellular ionic gradients, producing a net increased osmotic pressure, water influx, cell swelling and, eventually, osmotic lysis and release of inflammatory intracellular contents .
Occurs during pyroptosis, but lacks the nuclear integrity [7, 8] and oligonucleosomal DNA fragmentation patterns characteristic of apoptosis .
The inflammasome is a cytosolic multimeric signalling complex that coordinates the activation of an immune response against invading pathogens. Activation of the inflammasome subsequently leads to processing and activation of caspase-1 . Once activated, caspase-1 cleaves pro-IL-1β and pro-IL-18 into their mature forms, and it cleaves Gasdermin D (encoded by GSDMD) to induce pore opening and pyroptosis . The cytosolic pathogen recognition receptors capable of forming inflammasome complexes include NLRs, ALRs, and the tripartite motif (TRIM) family member Pyrin [3, 11].
Release of Activated IL-1β and IL-18.
The inflammatory cytokines IL-1β and IL-18 undergo caspase-1-dependent activation and secretion during pyroptosis. IL-1β is a potent endogenous pyrogen that stimulates fever, leukocyte tissue migration and the expression of a diverse array of cytokines and chemokines . IL-18 induces Interferon gamma (IFNγ) production and is important for the activation of T cells, macrophages and other cell types . Both IL-1β and IL-18 play crucial parts in the pathogenesis of a range of inflammatory and autoimmune diseases [12, 13]. Although neither cytokine is required for the process of cell death [14, 15], their production contributes to the inflammatory response elicited by cells undergoing pyroptosis.
The Signaling Cascades
TLR activation signals through the recruitment of specific adaptor molecules. Upon PAMP or DAMP recognition, TLRs recruit TIR-domain-containing adaptor proteins such as MyD88 and TRIF. MyD88 and TRIF then initiate signal transduction pathways that lead to the activation of NF-κB, IRFs, or MAP kinases, which subsequently regulate the expression of cytokines, chemokines, and type I IFN .
Cytosolic scaffolds can detect the presence of danger signals by directly detecting PAMPs or DAMPs, or indirectly detecting a secondary messenger. The scaffolds serve to recruit and oligomerize procaspase-1. Procaspase-1 recruitment can occur either directly or indirectly through the involvement of apoptosis-associated speck-like protein (ASC), which contains a caspase recruitment domain (CARD). Procaspase-1 is oligomerized into filaments that allow for its subsequent autoactivation. Active caspase-1 then functions to cleave pro-IL-1β and pro-IL-18, thus triggering their release into the extracellular space where they can exert an effect on immune cells, promoting both local and systemic immune responses .
Pyroptosis acts as a defense mechanism against infection by inducing inflammation. The formation of inflammasomes and the activity of caspase-1 determine the balance between eradication of the pathogen-associated disease state versus coping with a protracted infection. In a healthy cell, caspase-1 activation helps to fight infection. For example, caspase-1 induced pyroptotic cell death severely limits the internal spread of Salmonella and Shigella bacteria, via elimination of infected host cell incubators necessary for continued bacterial reproduction . When the danger signal is recognized, the infected quiescent cells become activated, undergoing pyroptosis and secreting inflammatory cytokines IL-1β and IL-18. IL-18 will stimulate IFNγ production and initiates the development of Th1 responses. Th1 responses tend to release cytokines that direct an immediate removal of the pathogen .
Highly conserved cell death processes such as pyroptosis can and will function as a double edge sword. Inflammasome activation results in an increase in cytokine levels, which will augment the consequences of inflammation. This in turn, contributes to the development of the adaptive immune response as infection progresses. The ultimate resolution will clear pathogens. In contrast, persistent inflammation has also been linked to a variety of autoimmune and autoinflammatory diseases such as multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, atherosclerosis, type 2 diabetes, and obesity [16, 17]. If the amplification cycles persist, metabolic disorder, auto-inflammatory diseases and liver injury associated with chronic inflammation will take place . Since pyroptosis is involved in many beneficial and detrimental inflammatory processes, this conserved cell death process remains an important area of continued study.
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