Myeloid PTEN promotes chemotherapy-induced NLRP3-inflammasome activation and antitumour immunity

Huang, Yi; Wang, Huanyu; Hao, Yize; Lin, Hualong; Dong, Menghao; Jin, Ye; Song, Lei; Wang, Yunzhi; Li, Qingqing; Shan, Baoen; Jiang, Yi‐Zhou; Li, Hongqi; Shao, Zhi-Ming; Kroemer, Guido; Zhang, Huafeng; Bai, Li; Jin, Tengchuan; Wang, Chao; Ma, Yuting; Cai, Yongping; Chen, Ding; Liu, Suling; Pan, Yueyin; Jiang, Wei; Zhou, Rongbin

doi:10.1038/s41556-020-0510-3

Cited by 84 publications

(72 citation statements)

References 68 publications

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“…A feature of the canonical NLRP3 inflammasome is its regulation by kinases such as TAK1, JNK (c-Jun N-terminal kinase) and protein kinase D (PKD) (6,45,46) and phosphatases such as protein phosphatase 2A (PP2A), protein tyrosine phosphatase non-receptor type 22 (PTPN22) (47) and PTEN (48). Whether these enzymes contribute to the NLRP3 priming, licencing, or activating step is not clear.…”

Section: Discussionmentioning

confidence: 99%

Priming Is Dispensable for NLRP3 Inflammasome Activation in Human Monocytes In Vitro

et al. 2020

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Interleukin (IL)-18 and IL-1b are potent pro-inflammatory cytokines that contribute to inflammatory conditions such as rheumatoid arthritis and Alzheimer's disease. They are produced as inactive precursors that are activated by large macromolecular complexes called inflammasomes upon sensing damage or pathogenic signals. NLRP3 inflammasome activation is regarded to require a priming step that causes NLRP3 and IL-1b gene upregulation, and also NLRP3 post-translational licencing. A subsequent activation step leads to the assembly of the complex and the cleavage of pro-IL-18 and pro-IL-1b by caspase-1 into their mature forms, allowing their release. Here we show that human monocytes, but not monocyte derived macrophages, are able to form canonical NLRP3 inflammasomes in the absence of priming. NLRP3 activator nigericin caused the processing and release of constitutively expressed IL-18 in an unprimed setting. This was mediated by the canonical NLRP3 inflammasome that was dependent on K + and Cl − efflux and led to ASC oligomerization, caspase-1 and Gasdermin-D (GSDMD) cleavage. IL-18 release was impaired by the NLRP3 inhibitor MCC950 and by the absence of NLRP3, but also by deficiency of GSDMD, suggesting that pyroptosis is the mechanism of release. This work highlights the readiness of the NLRP3 inflammasome to assemble in the absence of priming in human monocytes and hence contribute to the very early stages of the inflammatory response when IL-1b has not yet been produced. It is important to consider the unprimed setting when researching the mechanisms of NLRP3 activation, as to not overshadow the pathways that occur in the absence of priming stimuli, which might only enhance this response.

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Section: Discussionmentioning

confidence: 99%

Priming Is Dispensable for NLRP3 Inflammasome Activation in Human Monocytes In Vitro

et al. 2020

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“…Recently, Huang et al. demonstrated that dephosphorylation of NLRP3 at Tyr32 by the phosphatase PTEN is necessary to allow NLRP3 activation and subsequent antitumor activity in response to chemotherapy, highlighting the potential clinical importance of NLRP3 PTMs 53 . As illustrated in Fig.…”

Section: Phosphorylation Of Nlrp3mentioning

confidence: 99%

“…Several additional NLRP3 phosphorylation sites at Ser5, Tyr32, and Tyr861 appear to inhibit NLRP3 activity 49,51,53 . The kinases responsible for these modifications are currently unknown and so the potential impact of modulating their activity remains to be determined.…”

Section: Targeting Nlrp3 Phosphorylationmentioning

confidence: 99%

“…The kinases responsible for these modifications are currently unknown and so the potential impact of modulating their activity remains to be determined. However, the phosphatases involved in dephosphorylation of these sites have been identified as PP2A, PTEN and PTPN22, 49,51,53 and inhibiting these phosphatases will likely limit NLRP3 activation. Phosphatases were previously considered to be difficult drug targets, however a number of phosphatase inhibitors are now being evaluated in clinical trials 128 .…”

Section: Targeting Nlrp3 Phosphorylationmentioning

confidence: 99%

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NLRP3 inflammasome priming: A riddle wrapped in a mystery inside an enigma

McKee

Coll

2020

Journal of Leukocyte Biology

148

138

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The NLRP3 (NOD‐, LRR‐, and pyrin domain‐containing protein 3) inflammasome is an immunological sensor that detects a wide range of microbial‐ and host‐derived signals. Inflammasome activation results in the release of the potent pro‐inflammatory cytokines IL‐1β and IL‐18 and triggers a form of inflammatory cell death known as pyroptosis. Excessive NLRP3 activity is associated with the pathogenesis of a wide range of inflammatory diseases, thus NLRP3 activation mechanisms are an area of intensive research. NLRP3 inflammasome activation is a tightly regulated process that requires both priming and activation signals. In particular, recent research has highlighted the highly complex nature of the priming step, which involves transcriptional and posttranslational mechanisms, and numerous protein binding partners. This review will describe the current understanding of NLRP3 priming and will discuss the potential opportunities for targeting this process therapeutically to treat NLRP3‐associated diseases.

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“…Cell pyroptosis was a type of cell death featured by NLRP3 in ammasome activation and proin ammatory cytokines secretion [27,28], and induction of pyroptotic cell death was proved to be an effective strategy to eliminate cancer cells [29,30]. For example, myeloid phosphate and tension homology deleted on chromosome ten (PTEN) promoted chemotherapy-induced NLRP3 mediated cell pyroptosis to inhibit cancer development [30], and activation of NLRP3-mediated pyroptotic cell death enhanced the cytotoxic effects of cisplatin in non-small cell lung cancer (NSCLC) [29]. Of note, Bala et al validated that there existed an intrinsic PD-L1/NLRP3 signaling pathway in melanoma cells [31], and the correlations between PD-L1 and NLRP3 had also been observed in interferon-γ (IFN-γ) induced myotubes [32].…”

Section: Introductionmentioning

confidence: 99%

Low-dose Diosbulbin-B (DB) Regulates Tumor-Intrinsic PD-L1/NLRP3 Signaling Pathway to Increase Cisplatin-Sensitivity in Gastric Cancer (GC)

Qiu

Xue

2020

Preprint

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Background: Generation of cisplatin (DDP)-resistance by gastric cancer (GC) cells seriously limits the therapeutic efficacy of this drug in clinic, and recent data suggested that Diosbulbin-B (DB), the main anti-tumor compound of Dioscorea bulbifera L, was effective to improve cisplatin-sensitivity in GC cells. However, the underlying mechanisms are still largely unknown.Methods: Genes expressions were determined by Real-Time qPCR and Western Blot. Cell viability was evaluated by cell counting kit-8 and trypan blue staining assay. Annexin V-FITC/PI double staining assay was used to examine cell apoptosis. The Spheroid formation assay was used to evaluated cell stemness. Immunohistochemistry (IHC) was employed to examine the expressions and localization of Ki67 protein in mice tumor tissues.Results: Here we found that low-dose DB (12.5 μM) downregulated PD-L1 to activate NLRP3-medicated pyroptosis, and inhibited cancer stem cells (CSCs) properties, to sensitize cisplatin-resistant GC (CR-GC) cells to cisplatin. Mechanistically, the CR-GC cells were obtained, and either low-dose DB or cisplatin alone had little effects on cell viability in CR-GC cells, while low-dose DB significantly induced apoptotic cell death in cisplatin treated CR-GC cells. In addition, low-dose DB triggered cell pyroptosis in CR-GC cells stimulated with cisplatin, which were abrogated by silencing NLRP3. Next, CSCs tended to be enriched in CR-GC cells, instead of their parental cisplatin-sensitive GC (CS-GC) cells, and low-dose DB (12.5 μM) inhibited spheroid formation and stemness biomarkers (CD44, CD133, SOX2, OCT4 and Nanog) expressions to eliminate CSCs in CR-GC cells, which were reversed by upregulating programmed death ligand-1 (PD-L1). Furthermore, we proved that PD-L1 negatively regulated NLRP3 in CR-GC cells, and low-dose DB (12.5 μM) activated NLRP3-mediated pyroptotic cell death in cisplatin treated CR-GC cells by downregulating PD-L1. Also, low-dose DB aggravated the inhibiting effects of cisplatin on tumorigenesis of CR-GC cells in vivo. Conclusions: Collectively, low-dose DB (12.5 μM) regulated intrinsic PD-L1/NLRP3 pathway to improve cisplatin-sensitivity in CR-GC cells, and this study provided alternative therapy treatments for GC.

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Myeloid PTEN promotes chemotherapy-induced NLRP3-inflammasome activation and antitumour immunity

Cited by 84 publications

References 68 publications

Priming Is Dispensable for NLRP3 Inflammasome Activation in Human Monocytes In Vitro

Priming Is Dispensable for NLRP3 Inflammasome Activation in Human Monocytes In Vitro

NLRP3 inflammasome priming: A riddle wrapped in a mystery inside an enigma

Low-dose Diosbulbin-B (DB) Regulates Tumor-Intrinsic PD-L1/NLRP3 Signaling Pathway to Increase Cisplatin-Sensitivity in Gastric Cancer (GC)

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