Bruton tyrosine kinase deficiency augments NLRP3 inflammasome activation and causes IL-1β–mediated colitis

Mao, Liming; Kitani, Atsushi; Hiejima, Eitaro; Montgomery-Recht, Kim; Zhou, Wenchang; Fuss, Ivan J.; Wiestner, Adrian; Strober, Warren

doi:10.1172/jci128322

Cited by 74 publications

(72 citation statements)

References 38 publications

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“…Wang et al recently utilized HEK293T cells to prove that the stimulator of interferon genes (STING) binds to NLRP3 thus mediating its localization into the ER and determining its de-ubiquitination required for inflammasome activation [ 102 ]. Finally, Mao et al used HEK293T cells to demonstrate that Bruton tyrosine kinase (BTK) binds to NLRP3 to regulate its activation, therefore suggesting that BTK deficiency is associated with several inflammatory NLRP3-mediated diseases [ 103 ].…”

Section: Cell Models To Study Nlrp3 Inflammasome Biologymentioning

confidence: 99%

Cellular Models and Assays to Study NLRP3 Inflammasome Biology

Zito

Buscetta

Cimino

et al. 2020

IJMS

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The NLRP3 inflammasome is a multi-protein complex that initiates innate immunity responses when exposed to a wide range of stimuli, including pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). Inflammasome activation leads to the release of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 and to pyroptotic cell death. Over-activation of NLRP3 inflammasome has been associated with several chronic inflammatory diseases. A deep knowledge of NLRP3 inflammasome biology is required to better exploit its potential as therapeutic target and for the development of new selective drugs. To this purpose, in the past few years, several tools have been developed for the biological characterization of the multimeric inflammasome complex, the identification of the upstream signaling cascade leading to inflammasome activation, and the downstream effects triggered by NLRP3 activation. In this review, we will report cellular models and cellular, biochemical, and biophysical assays that are currently available for studying inflammasome biology. A special focus will be on those models/assays that have been used to identify NLRP3 inhibitors and their mechanism of action.

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Section: Cell Models To Study Nlrp3 Inflammasome Biologymentioning

confidence: 99%

Cellular Models and Assays to Study NLRP3 Inflammasome Biology

Zito

Buscetta

Cimino

et al. 2020

IJMS

View full text Add to dashboard Cite

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“…However, Mao et al. revealed that BTK deficiency augmented NLRP3 inflammasome activation by inhibiting the PP2A-mediated dephosphorylation of serine 5 in the pyrin domain of NLRP3 ( Mao et al., 2020 ). Hence, regulation of NLRP3 phosphorylation requires further investigations.…”

Section: Discussionmentioning

confidence: 99%

Hematopoietic Cell Kinase (HCK) Is Essential for NLRP3 Inflammasome Activation and Lipopolysaccharide-Induced Inflammatory Response In Vivo

et al. 2020

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Activation of the NLRP3 inflammasome results in caspase 1 cleavage, which subsequently leads to IL-1b and IL-18 secretion, as well as pyroptosis, and aberrant activation of the inflammasome is involved in several diseases such as type 2 diabetes, atherosclerosis, multiple sclerosis, Parkinson's disease, and Alzheimer's disease. NLRP3 activity is regulated by various kinases. Genetic and pharmacological inhibition of the hematopoietic cell kinase (HCK), a member of the Src family of non-receptor tyrosine kinases (NRTKs) primarily expressed in myeloid cells, has previously been shown to ameliorate inflammation, indicating that it may be involved in the regulation of microglia function. However, the underlying mechanism is not known. Hence, in this study, we aimed to investigate the role of HCK in NLRP3 inflammasome activation. We demonstrated that HCK silencing inhibited NLRP3 inflammasome activation. Furthermore, the HCK-specific inhibitor, A419259, attenuated the release of IL-1b and caspase 1(P20) from the macrophages and microglia and reduced the formation of the apoptosis-associated speck-like protein with a CARD domain (ASC) oligomer. We also observed that HCK binds to full length NLRP3 and its NBD (NACHT) and LRR domains, but not to the PYD domain. In vivo, the HCK inhibitor attenuated the LPS-induced inflammatory response in the liver of LPS-challenged mice. Collectively, these results suggested that HCK plays a critical role in NLRP3 inflammasome activation. Our results will enhance current understanding regarding the effectiveness of HCK inhibitors for treating acute inflammatory diseases.

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“…This activity of PP2A is inhibited by Bruton's tyrosine kinase (BTK) that binds to NLRP3 following LPS stimulation to prevent dephosphorylation of Ser5. This inhibition is relieved upon NLRP3 activation that triggers the dissociation of BTK and NLRP3 50 . Phosphorylation at Tyrosine 861 (Tyr861) of NLRP3 is also inhibitory and in resting cells prevents its aberrant activation.…”

Section: Phosphorylation Of Nlrp3mentioning

confidence: 99%

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

McKee

Coll

2020

Journal of Leukocyte Biology

147

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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Bruton tyrosine kinase deficiency augments NLRP3 inflammasome activation and causes IL-1β–mediated colitis

Cited by 74 publications

References 38 publications

Cellular Models and Assays to Study NLRP3 Inflammasome Biology

Cellular Models and Assays to Study NLRP3 Inflammasome Biology

Hematopoietic Cell Kinase (HCK) Is Essential for NLRP3 Inflammasome Activation and Lipopolysaccharide-Induced Inflammatory Response In Vivo

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

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