Human NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome activity is regulated by and potentially targetable through Bruton tyrosine kinase

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dc.contributor.advisor Weber, Alexander (Prof. Dr.)
dc.contributor.author Liu, Xiao
dc.date.accessioned 2018-09-17T06:23:03Z
dc.date.available 2018-09-17T06:23:03Z
dc.date.issued 2018-09-17
dc.identifier.other 511082703 de_DE
dc.identifier.uri http://hdl.handle.net/10900/84181
dc.identifier.uri http://nbn-resolving.de/urn:nbn:de:bsz:21-dspace-841815 de_DE
dc.identifier.uri http://dx.doi.org/10.15496/publikation-25571
dc.description.abstract The Nod-like receptor, NLRP3, has been described as a key immune sensor of microbial, environmental and endogenous insults or stress. The multimeric NLRP3 inflammasome recruits the adaptor protein ASC to activate caspase-1, leading to the maturation of the pro-inflammatory cytokines Interleukin (IL)-1β and IL-18. The NLRP3 inflammasome has a fundamental role in host defense against microbial pathogens but its deregulation is also implicated in sterile inflammation and the pathogenesis of several inflammatory diseases including Muckle-Wells Syndrome (MWS) caused by inherited NLRP3 mutations. NLRP3 inflammasome activity is tightly controlled to maintain immune homeostasis and avoid detrimental effects. However, the regulatory mechanism of this complex and medically relevant process are poorly understood. In this study, we identified Bruton’s tyrosine kinase (BTK), a non-receptor protein tyrosine kinase of the TEC family of proteins, as a novel regulator of the NLRP3 inflammasome by an unbiased triple SILAC phospho-proteomics. Further results revealed that pharmacological (using the Food and Drug Administration (FDA)-approved inhibitor, ibrutinib) and genetic (in BTK-mutated patients and Btk-knockout mice) BTK ablation attenuated caspase-1 activation and IL-1β maturation in response to Nigericin and the Staphylococcus aureus toxin, LukAB. Additionally, BTK directly interacted with NLRP3 and ASC, and promoted ASC speck formation and caspase-1 cleavage. Consistently, ibrutinib inhibited IL-1β release from immune cells of MWS patients. More importantly, obtained results from immune cells of ibrutinib therapy treated cancer patients provide evidence that in vivo application of ibrutinib affects IL-1ß processing and release in response to Nigericin. Thus, our data suggest that BTK is a critical regulator of NLRP3 inflammasome activation and that NLRP3 inflammasome-associated inflammatory diseases could potentially be targeted via BTK. en
dc.language.iso en de_DE
dc.publisher Universität Tübingen de_DE
dc.rights ubt-podok de_DE
dc.rights.uri http://tobias-lib.uni-tuebingen.de/doku/lic_mit_pod.php?la=de de_DE
dc.rights.uri http://tobias-lib.uni-tuebingen.de/doku/lic_mit_pod.php?la=en en
dc.subject.classification Immunbiologie de_DE
dc.subject.ddc 500 de_DE
dc.subject.ddc 610 de_DE
dc.subject.other NLRP3 inflammasome en
dc.subject.other regulation en
dc.subject.other Verordnung de_DE
dc.subject.other BTK de_DE
dc.title Human NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome activity is regulated by and potentially targetable through Bruton tyrosine kinase en
dc.type Dissertation de_DE
dcterms.dateAccepted 2018-07-31
utue.publikation.fachbereich Medizin de_DE
utue.publikation.fakultaet 4 Medizinische Fakultät de_DE

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