GSDMB is increased in IBD and regulates epithelial restitution/repair independent of pyroptosis

Rana, Nitish; Privitera, Giuseppe; Kondolf, Hannah; Bulek, Katarzyna; Lechuga, Susana; Salvo, Carlo De; Corridoni, Daniele; Antanaviciute, Agne; Maywald, Rebecca L.; Hurtado, Alexander; Zhao, Junjie; Huang, Emina H.; Li, Xiaoxia; Chan, E. Ricky; Simmons, Alison; Bamias, Giorgos; Abbott, Derek W.; Heaney, Jason D.; Ivanov, Andrei I.; Pizarro, Theresa T.

doi:10.1016/j.cell.2021.12.024

Cited by 134 publications

(136 citation statements)

References 75 publications

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“…Therefore, based on the above evidences proving the preclinical validity of GSDMB mouse models, and the overall similarity in GSDMB expression patterns between human and mouse tissues observed in our R26-GB2 mice, we propose that this strain could be also useful for deciphering the implication of GSDMB in other diseases, such as response to pathogens ( Hansen et al, 2021 ), and inflammatory pathologies (asthma, type-I diabetes, inflammatory bowel diseases, biliary cirrhosis, and rheumatoid arthritis) ( Li et al, 2012 ; Morrison et al, 2013 ; Söderman et al, 2015 ; Panganiban et al, 2018 ; Chen et al, 2019 ; Rana et al, 2022 ). In fact, using GEMM models, only the mechanistic implication of GSDMB3 has been demonstrated in asthma, while the GSDMB bactericidal function was not validated in GSDMB1 KI mice ( Hansen et al, 2021 ).…”

Section: Discussionmentioning

confidence: 76%

“…Finally, apart from cancer, GSDMB function has been implicated in the response to infection with Shigella enterobacteria ( Hansen et al, 2021 ) and in the pathobiology of diverse inflammatory diseases, including asthma, inflammatory bowel disease or arthritis, among others ( Li et al, 2012 ; Morrison et al, 2013 ; Söderman et al, 2015 ; Panganiban et al, 2018 ; Chen et al, 2019 ; Rana et al, 2022 ). Therefore, we investigated if R26-GB2 mice exhibited any pathological (non-cancer) phenotype at the microscopic level.…”

Section: Resultsmentioning

confidence: 99%

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Gasdermin-B Pro-Tumor Function in Novel Knock-in Mouse Models Depends on the in vivo Biological Context

Sarrió

Rojo-Sebastián

Teijo

et al. 2022

Front. Cell Dev. Biol.

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Gasdermins (GSDM) genes play complex roles in inflammatory diseases and cancer. Gasdermin-B (GSDMB) is frequently upregulated in human cancers, especially in HER2-amplified breast carcinomas, and can promote diverse pro-tumor functions (invasion, metastasis, therapy-resistance). In particular, the GSDMB shortest translated variant (isoform 2; GSDMB2) increases aggressive behavior in breast cancer cells. Paradoxically, GSDMB can also have tumor suppressor (cell death induction) effects in specific biological contexts. However, whether GSDMB has inherent oncogenic, or tumor suppressor function in vivo has not been demonstrated yet in preclinical mouse models, since mice lack GSDMB orthologue. Therefore, to decipher GSDMB cancer functions in vivo we first generated a novel knock-in mouse model (R26-GB2) ubiquitously expressing human GSDMB2. The comprehensive histopathological analysis of multiple tissues from 75 animals showed that nucleus-cytoplasmic GSDMB2 expression did not clearly affect the overall frequency nor the histology of spontaneous neoplasias (mostly lung carcinomas), but associated with reduced incidence of gastric tumors, compared to wildtype animals. Next, to assess specifically the GSDMB2 roles in breast cancer, we generated two additional double transgenic mouse models, that co-express GSDMB2 with either the HER2/NEU oncogene (R26-GB2/MMTV-NEU mice) or the Polyoma middle-T antigen (R26-GB2/MMTV-PyMT) in breast tumors. Consistent with the pro-tumor effect of GSDMB in HER2+ human breast carcinomas, R26-GB2/MMTV-NEU GSDMB2-positive mice have double breast cancer incidence than wildtype animals. By contrast, in the R26-GB2/MMTV-PyMT model of fast growing and highly metastatic mammary tumors, GSDMB2 expression did not significantly influence cancer development nor metastatic potential. In conclusion, our data prove that GSDMB2 in vivo pro-tumor effect is evidenced only in specific biological contexts (in concert with the HER2 oncogene), while GSDMB2 alone does not have overall intrinsic oncogenic potential in genetically modified mice. Our novel models are useful to identify the precise stimuli and molecular mechanisms governing GSDMB functions in neoplasias and can be the basis for the future development of additional tissue-specific and context-dependent cancer models.

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Section: Discussionmentioning

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Gasdermin-B Pro-Tumor Function in Novel Knock-in Mouse Models Depends on the in vivo Biological Context

Sarrió

Rojo-Sebastián

Teijo

et al. 2022

Front. Cell Dev. Biol.

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“…In addition, the full impact of GSDMs and how they may influence the inflammasome–microbiome axis in the pathogenesis of CRC has yet to be determined. Interestingly, altered GSDM expression is observed in IBD ( Bulek et al., 2020 ; Tan et al., 2020 ; Rana et al., 2022 ), in which dysbiosis is thought to exert a pathogenic role ( Ni et al., 2017 ). Ulcerative colitis and colonic Crohn’s disease are known to increase the risk of developing CRC, especially in the event of prolonged, uncontrolled inflammation ( Ullman and Itzkowitz, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

“…The implication of these findings is that GSDMB-mediated pyroptosis may promote CRC pathogenesis. Alternatively, a recent study implicates GSDMB-dependent non-pyroptotic functions in IEC, including proliferation, migration, and adhesion ( Rana et al., 2022 ), which when dysregulated could also potentially lead to tumorigenesis. Of note, GSDMB single nucleotide polymorphisms are linked to increased susceptibility to inflammatory bowel disease (IBD) ( Chao et al., 2017 ); as such, it is possible that GSDMB may play a role in CRC pathogenesis by promoting chronic intestinal inflammation, such as that observed in IBD.…”

Section: Inflammasome-mediated Gasdermin Activation and Impact Of The Microbiomementioning

confidence: 99%

“…Considering the well-established association between chronic intestinal inflammation and cancer ( Ullman and Itzkowitz, 2011 ), the hypothesis that GSDM-regulated inflammation may play a role in carcinogenesis is plausible and deserves careful consideration. Furthermore, recent evidence implicates GSDM activation in non-pyroptotic functions, including differentiation, proliferation, migration, and non-lytic release of inflammatory mediators, suggesting that the contribution of GSDMs in CRC might extend beyond pyroptosis ( Zou et al., 2021 ; Rana et al., 2022 ). Nonetheless, the interaction(s) between a dysregulated microbiome and GSDMs, as well as their contribution to the progression of microbiome-associated inflammation leading to CRC, is largely unknown.…”

Section: Introductionmentioning

confidence: 99%

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Novel Insights Into the Interactions Between the Gut Microbiome, Inflammasomes, and Gasdermins During Colorectal Cancer

Privitera

Rana

Scaldaferri

et al. 2022

Front. Cell. Infect. Microbiol.

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Colorectal cancer (CRC) is one of the most prevalent and deadly forms of cancer in Western countries. Inflammation is a well-known driver of colonic carcinogenesis; however, its role in CRC extends beyond colitis-associated cancer. Over the last decades, numerous associations between intestinal dysbiosis and CRC have been identified, with more recent studies providing mechanistic evidence of a causative relationship. Nonetheless, much remains to be discovered regarding the precise implications of microbiome alterations in the pathogenesis of CRC. Research confirms the importance of a bidirectional crosstalk between the gut microbiome and the mucosal immune system in which inflammasomes, multiprotein complexes that can sense “danger signals,” serve as conduits by detecting microbial signals and activating innate immune responses, including the induction of microbicidal activities that can alter microbiome composition. Current evidence strongly supports an active role for this “inflammasome–microbiome axis” in the initiation and development of CRC. Furthermore, the gasdermin (GSDM) family of proteins, which are downstream effectors of the inflammasome that are primarily known for their role in pyroptosis, have been recently linked to CRC pathogenesis. These findings, however, do not come without controversy, as pyroptosis is reported to exert both anti- and protumorigenic functions. Furthermore, the multi-faceted interactions between GSDMs and the gut microbiome, as well as their importance in CRC, have only been superficially investigated. In this review, we summarize the existing literature supporting the importance of the inflammasome–microbiota axis, as well as the activation and function of GSDMs, to gain a better mechanistic understanding of CRC pathogenesis.

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Sodium Butyrate Regulates Gasdermin B Exerted Protection Effect on the MTX‐Induced NCM460 and Hum Cells

Jiang,

Liu,

Chen

et al. 2023

Advanced Therapeutics

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Inflammatory bowel disease (IBD) is a complex disorder with unclear etiology, and the impact of short‐chain fatty acids (SCFAs) on its pathogenesis is not well‐studied. This research explores the potential protective effects of sodium butyrate (NaB) in inflammatory bowel disease (IBD) through the Gasdermin B (GSDMB) non‐pyroptotic pathway. Fecal SCFA levels and GSDMB‐related proteins of IBD patients are analyzed. NCM460 and HUM cells are treated with methotrexate (MTX) for 24 hours. NaB is applied at concentrations of 1, 5, and 10 mm mL−1 to cells. It is found that a decrease in SCFAs content, zonula occludens‐1 (ZO‐1), and Occludin expression, along with an increase in GSDMB, focal adhesion kinase (FAK), and extracellular singal‐regulated kinase (ERK) in IBD patients is observed. NaB, at medium and high concentrations, promotes cell viability and migration and increased GSDMB expression. The low concentration of NaB has a significant protective effect on IBD‐affected cells, activating the GSDMB non‐pyroptotic pathway. This protection diminishes after the GSDMB knockdown. The study reveals that NaB may play a crucial role in protecting intestinal epithelial integrity in IBD through the GSDMB non‐pyroptotic pathway. These findings underline the potential of targeting this pathway for therapeutic strategies, highlighting the importance of SCFAs in understanding and treating IBD.

show abstract

GSDMB is increased in IBD and regulates epithelial restitution/repair independent of pyroptosis

Cited by 134 publications

References 75 publications

Gasdermin-B Pro-Tumor Function in Novel Knock-in Mouse Models Depends on the in vivo Biological Context

Gasdermin-B Pro-Tumor Function in Novel Knock-in Mouse Models Depends on the in vivo Biological Context

Novel Insights Into the Interactions Between the Gut Microbiome, Inflammasomes, and Gasdermins During Colorectal Cancer

Sodium Butyrate Regulates Gasdermin B Exerted Protection Effect on the MTX‐Induced NCM460 and Hum Cells

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