The role of pyroptosis in the occurrence and development of pregnancy-related diseases

Abstract

Pyroptosis is a form of programmed cell death that is crucial in the development of various diseases, including autoimmune diseases, atherosclerotic diseases, cancer, and pregnancy complications. In recent years, it has gained significant attention in national and international research due to its association with inflammatory immune overactivation and its involvement in pregnancy complications such as miscarriage and preeclampsia (PE). The mechanisms discussed include the canonical pyroptosis pathway of gasdermin activation and pore formation (caspase-1-dependent pyroptosis) and the non-canonical pyroptosis pathway (cysteoaspartic enzymes other than caspase-1). These pathways work on various cellular and factorial levels to influence normal pregnancy. This review aims to summarize and analyze the pyroptosis pathways associated with abnormal pregnancies and pregnancy complications. The objective is to enhance pregnancy outcomes by identifying various targets to prevent the onset of pyroptosis.

Keywords: GDM; cell death; preeclampsia; pregnancy complications; pyroptosis.

Figure 1

Inflammatory and pathological consequences of pyroptosis (1). Pyroptosis, induced by Gasdermin D (GSDMD) pore formation, results in the release of proinflammatory cytokines, alarmins, and damage-associated molecular patterns (DAMPs). These inflammatory molecules act on bystander cells (e.g., endothelial cells, lymphocytes) to promote an inflammatory response. The resulting cell death and inflammation can disrupt the endothelial barrier in blood vessels and vital organs, such as the lungs, leading to leucocyte infiltration. GSDMD pore formation activates the coagulation cascade and can contribute to lethality from disseminated intravascular coagulation. Pyroptosis in neutrophils and other cells triggers NETosis. Improper neutrophil extracellular trap (NET) and aberrant NETosis and DAMP removal can further induce pyroptosis and tissue damage. Reproduced with permission from [Vasudevan SO, Behl B, Rathinam VA], [Pyroptosis-induced inflammation and tissue damage.]; published by [Semin Immunol], [2023].

Figure 2

Molecular mechanisms of pyroptotic cell death (16). (A) The sensing of cytosolic disturbances by NLRP3 (NLR family pyrin domain-containing 3) receptor recruits the adaptor protein apoptosis-associated speck-like protein containing (ASC) to a large aggregate platform (called the inflammasome) that serves as a site of caspase-1 activation. Active caspase-1 cleaves the 53-kDa GSDMD and generates a 31-kDa N-terminal pore-forming fragment that controls pyroptosis(Canonical model). GSDMD can also be processed via inflammasome-independent activation of caspase-11(Non-canonical model). In this pathway, caspase-11 in mice and caspase-4 and 5 in humans bind to and are activated by LPS released into the cytoplasm after gram-negative bacterial infection. Unlike cleaved caspase-1, cleaved caspase-11 does not convert pro-IL-1β and pro-IL-18 to their mature forms. Instead, the process of pyroptosis promotes K+ efflux to activate caspase-1-dependent maturation of the pro-inflammatory cytokines IL-1β and IL-18 after NLRP3 inflammasome activation, leading to cellular pyroptosis. (B) Besides GSDMD, there is also a gasdermin E (GSDME)-dependent pyroptosis. GSDME is cleaved by caspase-3 upon mitochondrial dysfunction or death receptor activation. The GSDME N-fragments promote cell swelling and lysis by forming pores in the plasma membrane. ASC, apoptosis-associated speck-like protein containing; LPS: lipopolysaccharide. Reproduced with permission from [Ketelut-Carneiro N, Fitzgerald KA. Apoptosis], [Pyroptosis, and Necroptosis-Oh My! The Many Ways a Cell Can Die.]; published by [J Mol Biol], [2022].

Figure 3

Schematic diagram illustrating the potential mechanism of action of TMBIM4 on PE pathogenesis (104). LPS induced the downregulation of TMBIM4 in the trophoblasts. TMBIM4 deficiency in the trophoblasts markedly enhanced the NLRP3 inflammasome activity and promoted subsequent pyroptosis, thereby disrupting trophoblast viability, migration, and invasion, and might be involved in the pathogenesis of PE. TMBIM4, transmembrane BAX inhibitor motif containing 4. Reproduced with permission from [Liu C], [TMBIM4 Deficiency Facilitates NLRP3 Inflammasome Activation-Induced Pyroptosis of Trophoblasts: A Potential Pathogenesis of Preeclampsia.)]; published by [Biology (Basel], [2023].

Figure 4

The role of pyroptosis in the occurrence and development of pregnancy-related diseases (Created with BioRender.com). (A) MHF may cause high blood pressure in adult offspring. It also lead to the down-regulation of fetal renal peroxisomal markers PEX3 and 14, decreased antioxidant SOD2 and catalase, and elevated oxidative stress marker Ephx2 (61); (B) PA can activate NLRP3 inflammatory vesicles, resulting in significant caspase-1 activation and IL-1β secretion (62); (C) HMGB1 activates the NF-κB signaling pathway, NLRP-3 inflammatory vesicle assembly, caspase-1 protein activation, and release of inflammatory factors, ultimately inducing aseptic inflammation. This leads to the disruption of the maternal-fetal interface and the development of URSA (68); (D) ZIKV infection can activate RIG-I, which recognizes the viral genome and causes placental cell pyroptosis. This leads to the release of TNF-α, which activates caspase-8 and caspase-3, resulting in the cleavage of GSDME in placental cells (73); (E) miR-124-3p mimics increased the expression of NLRP3, caspase1 and IL-1β (107); (F) Nrf2 deficiency upregulates GSDMD expression, thereby exacerbating maternal hypoxia-induced pyroptosis in IUGR offspring (123). MHF, high-fat maternal; PEX, peroxisomes; SOD2, Superoxide Dismutase 2; HMGB1, high mobility group box-1; ZIKV, Zika virus; Nrf2, Nuclear factor erythroid-derived 2-related factor 2.