Pyroptosis: mechanisms and diseases

Abstract

Currently, pyroptosis has received more and more attention because of its association with innate immunity and disease. The research scope of pyroptosis has expanded with the discovery of the gasdermin family. A great deal of evidence shows that pyroptosis can affect the development of tumors. The relationship between pyroptosis and tumors is diverse in different tissues and genetic backgrounds. In this review, we provide basic knowledge of pyroptosis, explain the relationship between pyroptosis and tumors, and focus on the significance of pyroptosis in tumor treatment. In addition, we further summarize the possibility of pyroptosis as a potential tumor treatment strategy and describe the side effects of radiotherapy and chemotherapy caused by pyroptosis. In brief, pyroptosis is a double-edged sword for tumors. The rational use of this dual effect will help us further explore the formation and development of tumors, and provide ideas for patients to develop new drugs based on pyroptosis.

Fig. 1

The timeline of pyroptosis

Fig. 2

Molecular mechanism of pyroptosis. In the canonical pathway, PAMPs and DAMPs receive intracellular signaling molecule stimulation and assemble with pro-caspase-1 and ASC to form inflammasomes and active caspase-1. Cleaved-caspase-1 cleaves GSDMD and pro-IL-1β/18. N-GSDMD perforates the cell membrane by forming nonselective pores, further causing water influx, lysis, and death. In addition, IL-1β and IL-18 are secreted from the pores formed by N-GSDMD. In the noncanonical pathway, cytosolic LPS activates caspase-4/5 and caspase-11, triggering pyroptosis by cleaving GSDMD. However, oxPAPC competes with LPS to bind caspase-4/1, thus inhibiting pyroptosis. In addition, the cleavage of GSDMD results in efflux of K⁺, ultimately mediating the assembly of NLRP3 inflammasome, resulting in the cleavage of pro-IL-1β and pro-IL-18. The activated caspase-11 also cleaves Pannexin-1, inducing ATP release and P2X7R-related pyroptotic cell death. In the caspase-3-mediated pathway, active caspase-3 cleaves GSDME to form N-GSDME, inducing pyroptosis. In the caspase-8-mediated pathway, inhibiting TAK1 induces the activation of caspase-8, which cleaves GSDMD, resulting in pyroptosis. In addition, under hypoxia conditions, PD-L1 is transferred to the nucleus and regulates the transcription of GSDMC together with p-Stat3, resulting in the conversion of apoptosis to pyroptosis after TNFα-activated caspase-8. In the granzyme-mediated pathway, CAR T cells rapidly activate caspase-3 in target cells by releasing GzmB, and then GSDME- was activated, causing extensive pyroptosis. In adittion, GzmA and GzmB in cytotoxic lymphocytes enter target cells through perforin and induce pyroptosis. GzmA hydrolyzes GSDMB, and GzmB directly activates GSDME

Fig. 3

Multiple assembly mechanisms of canonical inflammasomes. The assembly of canonical inflammasomes occurs in response to PAMPs and DAMPs. Inflammasome sensors have interaction with different target ligand. Bacillus anthracis toxin activates the NLRP1 inflammasome, and NLRP1 recruits pro-caspase-1 into the complex via ASC or direct contact with CARD-CARD interactions. A variety of PAMPs and DAMPs activate NLRP3 inflammasome, which is followed by the recruitment of ASC and pro-caspase-1. Human NAIP senses both bacterial flagellin and proteins of T3SS components. Mouse NAIP1, NAIP2 and NAIP5/6 sense needle, inner rod, and flagellin respectively to assemble and activate the NLRC4 inflammasome. NLRC4 activates caspase-1 in an ASC-dependent or ASC-independent manner. AIM2 inflammasome is assembled when AIM2 senses host- or pathogen-derived dsDNA. The pyrin inflammasome is activated by Rho-modifying proteins. Both AIM2 and pyrin activate caspase-1 in an ASC-dependent manner. Activated caspase-1 can not only cleave GSDMD to form N-GSDMD and induce pyroptosis, but also process the precursors of IL-1β/IL-18 to mature IL-1β/IL-18, which are released through the pores formed by N-GSDMD

Fig. 4

Current status of gasdermin-mediated tumor therapy. The desilylation of Phe-BF3 releases gasdermin from NP-GSDMA3 and induces pyroptosis. A bioorthogonal chemical system was developed in which Phe-BF3 can enter cells through LAT1 (a Phe-BF3 transporter), desilylate and cleave the design linker containing a silyl ether. The purified GSDMA3 (N + C) is conjugated with nanoparticles to become NP-GSDMA3. When Phe-BF3 binds to nanoparticles, the desilylation catalyzed by Phe-BF3 can release active gasdermin from the conjugated nanoparticles and selectively release active gasdermin. Chemotherapeutic drugs induce caspase-3-mediated pyroptosis in tumor cells with high GSDME expression and apoptosis in tumor cells with low expression of GSDME. Decitabine is an inhibitor of DNA methyltransferase, which can demethylate GSDME, changing GSDME expression from low to high, and shift apoptosis to pyroptosis. Almost all chemotherapeutic drugs can induce PD-L1 into the nucleus and promote the expression of GSDMC, but only the antibiotics such as daunorubicin, doxorubicin, epirubicin, and actinomycin D can also activate caspase-8, cause GSDMC cleavage and trigger pyroptosis. Pyroptosis is accompanied by the release of cytokines, which mediate the immune response

Fig. 5

Positive feedback loops of pyroptosis and immune response. After the occurrence of pyroptosis, the formed pores release inflammatory factors, such as Il-1β, HMGB1 LDH, and ATP, which act as alarm signals to activate and recruit immune cells and mediate the immune response. BRAF + MEK inhibitors induce GSDME-dependent pyroptosis mediated by caspase-3, and cause an increase in CD4+ T cell and CD8+ T cell infiltration and a decrease in MDSC and TAM. Cytotoxic lymphocytes release perforin and granzyme, and perforin forms pores in tumor cells. Granzyme enters tumor cells through these pores. GzmA cleaves GSDMB, and GzmB cleaves GSDME, further inducing pyroptosis. This forms a positive feedback loop, which means that a small number of cancer cells undergoing pyroptosis can trigger a tumor immune response and expand the death response

Fig. 6

The status of current NLRP3 inflammasome and caspase-1 inhibitors