Human NLRP3 inflammasome activity is regulated by and potentially targetable via BTK

Publication date: Available online 16 February 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Xiao Liu, Tica Pichulik, Olaf-Oliver Wolz, Truong-Minh Dang, Andrea Stutz, Carly Dillen, Magno Delmiro Garcia, Helene Kraus, Sabine Dickhöfer, Ellen Daiber, Lisa Münzenmayer, Silke Wahl, Nikolaus Rieber, Jasmin Kümmerle-Deschner, Amir Yazdi, Mirita Franz-Wachtel, Boris Macek, Markus Radsak, Sebastian Vogel, Berit Schulte, Juliane Sarah Walz, Dominik Hartl, Eicke Latz, Stephan Stilgenbauer, Bodo Grimbacher, Lloyd Miller, Cornelia Brunner, Christiane Wolz, Alexander N.R. Weber
BackgroundThe Nod-like receptor, NACHT, LRR and PYD domains-containing protein 3 (NLRP3), and Bruton's tyrosine kinase (BTK) are protagonists in innate and adaptive immunity, respectively: NLRP3 senses exogenous and endogenous insults leading to inflammasome activation, which occurs spontaneously in Muckle-Wells Syndrome (MWS); BTK mutations cause the genetic immunodeficiency X-linked agammaglobulinemia (XLA). However, to date few proteins that regulate NLRP3 inflammasome activity in human primary immune cells have been identified and clinically promising pharmacological targeting strategies remain elusive.ObjectiveWe therefore sought to identify novel regulators of the NLRP3 inflammasome in human cells with a view to exploring interference with inflammasome activity at the level of such regulators.MethodsFollowing proteome-wide phospho-proteomics, an identified novel regulator, BTK, was studied in human and murine cells using pharmacological and genetic BTK ablation.ResultsWe here show that BTK is a critical regulator of NLRP3 inflammasome activation: Pharmacological (using the Food and Drug Administration (FDA)-approved inhibitor, ibrutinib) and genetic (in XLA patients and Btk-knockout mice) BTK ablation in primary immune cells led to reduced Interleukin (IL)-1β processing and secretion in response to Nigericin and the Staphylococcus aureus toxin, Leukocidin (Luk) AB. BTK affected Apoptosis-associated speck-like protein containing a CARD (ASC) speck formation and caspase-1 cleavage and interacted with NLRP3 and ASC. S. aureus infection control in vivo and IL-1β release from MWS patient cells were impaired by ibrutinib. Notably, IL-1β processing and release from immune cells isolated from cancer patients on ibrutinib therapy was reduced.ConclusionOur data suggest that XLA may partially result from genetic inflammasome deficiency and that NLRP3 inflammasome-linked inflammation could potentially be targeted pharmacologically via BTK.

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Teaser

We show a critical and potentially therapeutically tractable role for BTK in NLRP3 inflammasome regulation in human primary cells.


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