Posttranslational and Therapeutic Control of Gasdermin-Mediated Pyroptosis and Inflammation

Fischer, Fabian A.; Chen, Kaiwen; Bezbradica, Jelena S.

doi:10.3389/fimmu.2021.661162

Cited by 48 publications

(36 citation statements)

References 101 publications

(162 reference statements)

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“…Canonical and noncanonical pyroptosis are associated with GSDMD cleavage. The N-terminal fragment of GSDMD (GSDMD-NT) binds phospholipids on the plasma membrane and oligomerizes to form functional pores [ 40 ]. GSDMD pore formation causes mitochondrial dysfunction, cell ballooning, cell rupture, IL-1 β release, and eventually the release of high mobility group 1 protein and ASC specks [ 36 , 40 ].…”

Section: Relevance Of Pyroptosis In Corneal Diseasesmentioning

confidence: 99%

Roles and Mechanisms of Regulated Necrosis in Corneal Diseases: Progress and Perspectives

Lin

Chen

Cissé

et al. 2022

Journal of Ophthalmology

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Regulated necrosis is defined as cell death characterized by loss of the cell membrane integrity and release of the cytoplasmic content. It contributes to the development and progression of some diseases, including ischemic stroke injury, liver diseases, hypertension, and cancer. Various forms of regulated necrosis, particularly pyroptosis, necroptosis, and ferroptosis, have been implicated in the pathogenesis of corneal disease. Regulated necrosis of corneal cells enhances inflammatory reactions in the adjacent corneal tissues, leading to recurrence and aggravation of corneal disease. In this review, we summarize the molecular mechanisms of pyroptosis, necroptosis, and ferroptosis in corneal diseases and discuss the roles of regulated necrosis in inflammation regulation, tissue repair, and corneal disease outcomes.

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Section: Relevance Of Pyroptosis In Corneal Diseasesmentioning

confidence: 99%

Roles and Mechanisms of Regulated Necrosis in Corneal Diseases: Progress and Perspectives

Lin

Chen

Cissé

et al. 2022

Journal of Ophthalmology

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“…Pyroptosis is one of the main mechanisms of cell death and causes an acute inflammatory response by activating inflammasomes and releasing inflammatory cytokines (7). Previous studies have demonstrated that pyroptosis is involved in the occurrence and development of infectious diseases, cardiovascular diseases, cancer and numerous other diseases (8)(9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Role of tumor necrosis factor receptor‑associated factor 6 in pyroptosis during acute pancreatitis

et al. 2021

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Acute pancreatitis (AP) is hypothesized to be related to the activation of an inflammatory response induced by pyroptosis. The aim of the present study was to investigate the potential role of tumor necrosis factor receptor-associated factor 6 (TRAF6) in pyroptosis in an AP rat model and the human pancreatic ductal epithelial HPDE6C7 cell line. In vivo, AP was induced by intraperitoneal injection of caerulein (CAE) in rats. The rats were sacrificed at 24 or 48 h after the final CAE injection. In vitro, HPDE6C7 cells were treated with CAE for 12, 24 and 48 h. Moreover, TRAF6 was overexpressed and treated with CAE for 48 h. Histopathological changes of pancreatic, serum and supernatant inflammatory cytokines and pyroptosis-related mRNA and protein expression levels were determined by histopathological scores, ELISA, reverse transcription-quantitative PCR and western blotting. In addition, pyroptosis morphological changes were also determined by Hoechst/PI staining in HPDE6C7 cells. Results showed that AP was observed in the CAE-induced rat model, and that serum IL-1β and IL-18 levels, and TRAF6, NLR pyrin domain containing 3 (NLRP3), caspase-1 and caspase-3 mRNA and protein expression levels were increased. Similar in HPDE6C7 cells, CAE treatment caused supernatant IL-1β level, NLRP3 and caspase-1 mRNA expression levels to significantly increase. After TRAF6 overexpression and CAE treatment, supernatant IL-1β level, caspase-1 protein expression level, and NLRP3 and caspase-3 mRNA and protein expression levels were also significantly increased. Furthermore, cells exhibited red fluorescence in Hoechst/PI staining, which can be used as a method of detecting pyroptosis activation. The results also showed that the red fluorescence was stronger after CAE treatment or TRAF6 overexpression plus CAE treatment. In conclusion, TRAF6 and caspase-1/3 signaling pathways were involved in the pathogenesis of CAE-induced AP in rats. Pyroptosis was activated by CAE and TRAF6 overexpression via the caspase-1/3 signaling pathways in HPDE6C7 cells.

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“…Activation of NLRP3 is regulated transcriptionally, to control messenger RNA (mRNA) expression ( 16 , 17 ), posttranscriptionally, to control mRNA stability ( 18 ), and by several posttranslational modifications (PTMs), to control protein activity ( 8 , 19 ). The latter are critical especially in chronic conditions where persistent NLRP3 expression occurs and NLRP3 transcriptional control is lost ( 20 – 22 ).…”

mentioning

confidence: 99%

TBK1 and IKKε act like an OFF switch to limit NLRP3 inflammasome pathway activation

Fischer

Mies

Nizami

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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NACHT, LRR, and PYD domains–containing protein 3 (NLRP3) inflammasome activation is beneficial during infection and vaccination but, when uncontrolled, is detrimental and contributes to inflammation-driven pathologies. Hence, discovering endogenous mechanisms that regulate NLRP3 activation is important for disease interventions. Activation of NLRP3 is regulated at the transcriptional level and by posttranslational modifications. Here, we describe a posttranslational phospho-switch that licenses NLRP3 activation in macrophages. The ON switch is controlled by the protein phosphatase 2A (PP2A) downstream of a variety of NLRP3 activators in vitro and in lipopolysaccharide-induced peritonitis in vivo. The OFF switch is regulated by two closely related kinases, TANK-binding kinase 1 (TBK1) and I-kappa-B kinase epsilon (IKKε). Pharmacological inhibition of TBK1 and IKKε, as well as simultaneous deletion of TBK1 and IKKε, but not of either kinase alone, increases NLRP3 activation. In addition, TBK1/IKKε inhibitors counteract the effects of PP2A inhibition on inflammasome activity. We find that, mechanistically, TBK1 interacts with NLRP3 and controls the pathway activity at a site distinct from NLRP3-serine 3, previously reported to be under PP2A control. Mutagenesis of NLRP3 confirms serine 3 as an important phospho-switch site but, surprisingly, reveals that this is not the sole site regulated by either TBK1/IKKε or PP2A, because all retain the control over the NLRP3 pathway even when serine 3 is mutated. Altogether, a model emerges whereby TLR-activated TBK1 and IKKε act like a “parking brake” for NLRP3 activation at the time of priming, while PP2A helps remove this parking brake in the presence of NLRP3 activating signals, such as bacterial pore-forming toxins or endogenous danger signals.

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Posttranslational and Therapeutic Control of Gasdermin-Mediated Pyroptosis and Inflammation

Cited by 48 publications

References 101 publications

Roles and Mechanisms of Regulated Necrosis in Corneal Diseases: Progress and Perspectives

Roles and Mechanisms of Regulated Necrosis in Corneal Diseases: Progress and Perspectives

Role of tumor necrosis factor receptor‑associated factor 6 in pyroptosis during acute pancreatitis

TBK1 and IKKε act like an OFF switch to limit NLRP3 inflammasome pathway activation

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