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

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 SchulteJuliane Sarah Walz, Dominik Hartl, Eicke Latz, Stephan Stilgenbauer, Bodo Grimbacher, Lloyd Miller, Cornelia Brunner, Christiane Wolz, Alexander N.R. Weber

Research output: Contribution to journalArticlepeer-review

Abstract

Background: The Nod-like receptor NACHT, LRR, and PYD domain–containing protein 3 (NLRP3) and Bruton 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 patients with Muckle-Wells syndrome; 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 pharmacologic targeting strategies remain elusive. Objective: We 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. Methods: After proteome-wide phosphoproteomics, the identified novel regulator BTK was studied in human and murine cells by using pharmacologic and genetic BTK ablation. Results: Here we show that BTK is a critical regulator of NLRP3 inflammasome activation: pharmacologic (using the US Food and Drug Administration–approved inhibitor ibrutinib) and genetic (in patients with XLA and Btk knockout mice) BTK ablation in primary immune cells led to reduced IL-1β processing and secretion in response to nigericin and the Staphylococcus aureus toxin leukocidin AB (LukAB). 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 cells of patients with Muckle-Wells syndrome were impaired by ibrutinib. Notably, IL-1β processing and release from immune cells isolated from patients with cancer receiving ibrutinib therapy were reduced. Conclusion: Our data suggest that XLA might result in part from genetic inflammasome deficiency and that NLRP3 inflammasome–linked inflammation could potentially be targeted pharmacologically through BTK.

Original languageEnglish (US)
Pages (from-to)1054-1067.e10
JournalJournal of Allergy and Clinical Immunology
Volume140
Issue number4
DOIs
StatePublished - Oct 2017

Keywords

  • Bruton tyrosine kinase
  • IL-1
  • Muckle-Wells syndrome
  • NLRP3
  • Staphylococcus aureus
  • X-linked agammaglobulinemia
  • ibrutinib
  • inflammasome
  • inflammation
  • macrophage

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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