Brd4 regulates NLRC4 inflammasome activation by facilitating IRF8-mediated transcription of <i>Naips</i>

Dong, Xingchen; Hu, Xiangming; Bao, Yan; Li, Guo; Yang, Xiaodong; Slauch, James M.; Chen, Linfeng

doi:10.1083/jcb.202005148

Cited by 16 publications

(21 citation statements)

References 53 publications

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“…Of interest, BRD4 might not participate in the activation of NLRP3 in bone marrow-derived macrophages (BMDMs), but it is an important regulator for the NLRC4 inflammasome activation in response to S. typhimurium infection. This is possibly due to BRD4 selectively activates a subset of NF-κB target genes (Dong et al, 2021). Nevertheless, the precise molecular mechanisms by which BRD4 promotes pyroptosis in ALD remain as an interesting open question, which is worthy of further investigation.…”

Section: Discussionmentioning

confidence: 99%

Sinapic Acid Reduces Oxidative Stress and Pyroptosis via Inhibition of BRD4 in Alcoholic Liver Disease

et al. 2021

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Alcoholic liver disease (ALD) is one of the main causes of death in chronic liver disease. Oxidative stress and pyroptosis are important factors leading to ALD. Bromodomain-containing protein 4 (BRD4) is a factor that we have confirmed to regulate ALD. As a phenolic acid compound, sinapic acid (SA) has significant effects in antioxidant, anti-inflammatory and liver protection. In this study, we explored whether SA regulates oxidative stress and pyroptosis through BRD4 to play a protective effect in ALD. Male C57BL/6 mice and AML-12 cells were used for experiments. We found that SA treatment largely abolished the up-regulation of BRD4 and key proteins of the canonical pyroptosis signalling in the liver of mice fed with alcohol, while conversely enhanced the antioxidant response. Consistantly, both SA pretreatment and BRD4 knockdown inhibited oxidative stress, pyroptosis, and liver cell damage in vitro. More importantly, the expression levels of BRD4 and pyroptosis indicators increased significantly in ALD patients. Molecule docking analysis revealed a potent binding of SA with BRD4. In conclusion, this study demonstrates that SA reduces ALD through BRD4, which is a valuable lead compound that prevents the ALD process.

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Section: Discussionmentioning

confidence: 99%

Sinapic Acid Reduces Oxidative Stress and Pyroptosis via Inhibition of BRD4 in Alcoholic Liver Disease

et al. 2021

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“…WNK1 can decelerate NLRP3 activation by balancing intracellular Cl- and K+ concentrations ( Mayes-Hopfinger et al, 2021 ). BRD4 has the ability to regulate NLRC4 inflammasome activation by facilitating the transcription of Naips ( Dong et al, 2021 ). Finally, we established an improved PR gene set consisting of 45 members ( Supplementary Table S1 ).…”

Section: Methodsmentioning

confidence: 99%

“…Third, as recently mentioned by Ruan et al (2020) and Fang et al (2020), there is a bypass pathway responsible for regulating pyroptosis, in which TLR3, TLR4, RIPK1, DIABLO (Smac), CASP8, and GSDMD participate in. Fourth, several new findings expand pyroptosis regulatory members (Linder et al, 2020;Dong et al, 2021;Mayes-Hopfinger et al, 2021). CARD8 has been identified as a new inflammasome to trigger pyroptosis (Linder et al, 2020).…”

Section: Improved Pyroptosis-related Gene Setmentioning

confidence: 95%

Pyroptosis-Related Risk Signature Exhibits Distinct Prognostic, Immune, and Therapeutic Landscapes in Hepatocellular Carcinoma

Zhao

Song²,

et al. 2022

Front. Genet.

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Background: Hepatocellular carcinoma (HCC) is a common abdominal cancer. The existing therapeutic approaches often fail to achieve satisfactory results. Pyroptosis, an inflammatory form of programmed cell death, provides new ideas for anticancer treatment. However, the roles of pyroptosis-related (PR) genes (PRGs) in HCC remain elusive.Methods: Differentially expressed genes (DEGs) (n = 22) were screened out using TCGA and GTEx databases. A novel PR risk signature was constructed through Lasso regression analysis. Its prognostic value was evaluated through a series of survival analyses and was tested in ICGC and GSE14520 cohorts. CIBERSORT, ssGSEA, and ESTIMATE methods were employed to determine the effects of the PR risk score on the tumor immune microenvironment (TIM). The TIDE scoring system, IMvigor210 cohort, GSE109211 dataset, and GSDC database were applied to explore the associations of the PR risk score with therapeutic effects. The biofunctions of WNK1 in hepatocellular cancer (HC) cells were confirmed through qPCR, colony formation, and Transwell assays.Results: Overall, 22 of 45 PRGs (48.9%) were abnormally expressed in HCC samples. Then, a PR risk signature consisting of eight PRGs was constructed. A high PR risk score led to an unfavorable prognosis. The PR risk score was identified as an independent prognostic factor of HCC and could increase the decision-making benefit of the traditional TNM model. In addition, we established a nomogram containing the clinical stage and PR risk score to predict the survival rates of HCC patients. The prognostic value of the PR model was successfully validated in ICGC and GSE14520 cohorts. Moreover, high PR risk conferred the decreased infiltration level of CD8+ T cells and weakened the activities of “cytolytic activity” pathways. As for therapeutic correlation, a high PR risk score seemed to imply a poor efficacy of PD-1/L1 inhibitors and sorafenib. Finally, the overexpression of WNK1 could promote the proliferation, migration, and invasion of HC cells.Conclusions: The PR risk score was closely related to the prognosis, antitumor immune process, therapeutic outcomes, and malignant progression of HCC. WNK1, the core regulator of pyroptosis, possesses pro-oncogenic abilities, showing promise as a novel treatment target.

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“…Several IRF members e.g. IRF-1, IRF-6, IRF-7 and IRF-8 are able to increase the expression of some pro-inflammatory cytokines and chemokines, and closely related to inflammatory diseases 38 - 45 . For example, up-regulated IRF-1 promotes liver ischemia/reperfusion injury after transplant, and the mechanism involves in elevating IL-15/IL-15Rα production in hepatocytes and accumulation of NK, NKT, and CD8 + T cells in liver tissues 43 .…”

Section: Discussionmentioning

confidence: 99%

Sublytic C5b-9 Induces CCL3/4 Production and Macrophage Accumulation in Thy-1N Rats via PKC-α/p65/IRF-8 Axis

Wang¹,

Qian²,

Zhao³

et al. 2022

Int. J. Biol. Sci.

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Mesangioproliferative glomerulonephritis (MsPGN) is a common human kidney disease. Rat Thy-1 nephritis (Thy-1N) is an animal model widely used for the study of MsPGN. Thy-1N is not only sublytic C5b-9-dependent, but also related to pro-inflammatory cytokine production and macrophage (Mφ) accumulation in rat renal tissues. In this study, we found that the expression or phosphorylation of chemokine CCL3/4, CD68 (Mφ marker), IRF-8, PKC-α and NF-κB-p65 (p65) were all up-regulated both in the renal tissues of Thy-1N rats ( in vivo ) and in the glomerular mesangial cells (GMCs) upon sublytic C5b-9 stimulation ( in vitro ). Further experiments in vitro revealed that the phosphorylated PKC-α (p-PKC-α) could promote p65 phosphorylation, and then p-p65 enhanced IRF-8 expression through binding to IRF-8 promotor (-591 ~ -582 nt and -299 ~ -290 nt). Additionally, up-regulation or silencing of IRF-8 gene promoted or reduced CCL3/4 production, and then regulated Mφ chemotaxis. The underlying mechanism involved in IRF-8 binding to CCL3 promoter (-249 ~ -236 nt), which resulted in CCL3 gene transcription. The experiments in vivo showed that knockdown of renal PKC-α, p65, IRF-8 and CCL3/4 genes could inhibit CCL3/4 production, Mφ accumulation, GMC proliferation and proteinuria of Thy-1N rats. Furthermore, p-PKC-α, p-p65, IRF-8, CCL3/4 expression and Mφ accumulation were also increased in the renal tissues of MsPGN patients. Collectively, these findings indicate that sublytic C5b-9 induces CCL3/4 production and Mφ accumulation via PKC-α/p65/IRF-8 axis, and finally aggravates the pathological changes of MsPGN.

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Brd4 regulates NLRC4 inflammasome activation by facilitating IRF8-mediated transcription of Naips

Cited by 16 publications

References 53 publications

Sinapic Acid Reduces Oxidative Stress and Pyroptosis via Inhibition of BRD4 in Alcoholic Liver Disease

Sinapic Acid Reduces Oxidative Stress and Pyroptosis via Inhibition of BRD4 in Alcoholic Liver Disease

Pyroptosis-Related Risk Signature Exhibits Distinct Prognostic, Immune, and Therapeutic Landscapes in Hepatocellular Carcinoma

Sublytic C5b-9 Induces CCL3/4 Production and Macrophage Accumulation in Thy-1N Rats via PKC-α/p65/IRF-8 Axis

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