Gasdermin D–mediated release of IL-33 from senescent hepatic stellate cells promotes obesity-associated hepatocellular carcinoma

Abstract

Long-term senescent cells exhibit a secretome termed the senescence-associated secretory phenotype (SASP). Although the mechanisms of SASP factor induction have been intensively studied, the release mechanism and how SASP factors influence tumorigenesis in the biological context remain unclear. In this study, using a mouse model of obesity-induced hepatocellular carcinoma (HCC), we identified the release mechanism of SASP factors, which include interleukin-1β (IL-1β)– and IL-1β–dependent IL-33, from senescent hepatic stellate cells (HSCs) via gasdermin D (GSDMD) amino-terminal–mediated pore. We found that IL-33 was highly induced in senescent HSCs in an IL-1β–dependent manner in the tumor microenvironment. The release of both IL-33 and IL-1β was triggered by lipoteichoic acid (LTA), a cell wall component of gut microbiota that was transferred and accumulated in the liver tissue of high-fat diet–fed mice, and the release of these factors was mediated through cell membrane pores formed by the GSDMD amino terminus, which was cleaved by LTA-induced caspase-11. We demonstrated that IL-33 release from HSCs promoted HCC development via the activation of ST2-positive T reg cells in the liver tumor microenvironment. The accumulation of GSDMD amino terminus was also detected in HSCs from human NASH-associated HCC patients, suggesting that similar mechanism could be involved in a certain type of human HCC. These results uncover a release mechanism for SASP factors from sensitized senescent HSCs in the tumor microenvironment, thereby facilitating obesity-associated HCC progression. Furthermore, our findings highlight the therapeutic potential of inhibitors of GSDMD-mediated pore formation for HCC treatment.

IL-33 induces thymic involution-associated naive T cell aging and impairs host control of severe infection

“…Besides cellular damage, accumulating evidence support that membrane pores are also involved in the release of IL-33 from cells 28 . For instance, recent reports show that IL-33 can be released from dendritic cells, intestinal epithelial cells, and hepatic stellate cells via membrane pores driven by perforin-2, gasdermin C, and gasdermin D, respectively [46][47][48] . However, the major cellular source and exact release mechanism of IL-33 during infection-induced thymic involution warrant further investigation.…”

The Role of Gasdermin-D-Mediated Pyroptosis in Organ Injury and Its Therapeutic Implications

“…There are few studies investigating the role of GSDMD in hepatic stellate cells, liver sinusoidal endothelial cells and Kupffer cells. Yamagishi et al 38 demonstrated that GSDMD-NT cell membrane pore formation mediates the release of IL-33 from senescent hepatic stellate cells, which promotes obesity-associated hepatocellular carcinoma. Interestingly, one study showed that GSDMD specific deficiency in myeloid cells is protective hepatic-ischemia reperfusion injury (IRI), with no protective effects in GSDMD specific deficiency in hepatocytes cells.…”

“…GSDMD deficiency in hepatoprotective in various liver injuries includes, but is not limited to, NAFLD, ALI, ALF, and 70% PH. In addition, GSDMD deficiency further inhibits DIC in sepsis in the liver microvasculature and protects against obesity-induced HCC 38 , 40 . However, further studies are needed to determine how GSDMD-mediated pyroptosis leads to liver injury and disease and investigate its effect in different liver cell types, including stellate and parenchymal cells.…”

“… 29 The NETs translocate to the lung and lead to neutrophil-platelet aggregation. 29 Vats et al 29 further showed that inhibition of GSDMD using GSDMD-NT inhibitors Necrosulfamide and LDC7559, pan-caspase inhibitor Z-VAD-FMK 38 alleviated lung vaso-occlusion in SCD.…”

The Related Metabolic Diseases and Treatments of Obesity

“…Obesity has been identified to promote most cancer progression, including breast cancer [ 47 , 48 ], HCC [ 49 , 50 ], and pancreatic ductal adenocarcinoma (PDAC) [ 51 , 52 ]. Insulin resistance, adipose inflammation, and tumor-promoting growth factors such as fibroblast growth factor 1 (FGF1) are closely associated with most cancer progression [ 47 ].…”