TY - JOUR
T1 - Human NACHT, LRR, and PYD domain–containing protein 3 (NLRP3) inflammasome activity is regulated by and potentially targetable through Bruton tyrosine kinase
AU - Liu, Xiao
AU - Pichulik, Tica
AU - Wolz, Olaf Oliver
AU - Dang, Truong Minh
AU - Stutz, Andrea
AU - Dillen, Carly
AU - Delmiro Garcia, Magno
AU - Kraus, Helene
AU - Dickhöfer, Sabine
AU - Daiber, Ellen
AU - Münzenmayer, Lisa
AU - Wahl, Silke
AU - Rieber, Nikolaus
AU - Kümmerle-Deschner, Jasmin
AU - Yazdi, Amir
AU - Franz-Wachtel, Mirita
AU - Macek, Boris
AU - Radsak, Markus
AU - Vogel, Sebastian
AU - Schulte, Berit
AU - Walz, Juliane Sarah
AU - Hartl, Dominik
AU - Latz, Eicke
AU - Stilgenbauer, Stephan
AU - Grimbacher, Bodo
AU - Miller, Lloyd
AU - Brunner, Cornelia
AU - Wolz, Christiane
AU - Weber, Alexander N.R.
N1 - Publisher Copyright:
© 2017 American Academy of Allergy, Asthma & Immunology
PY - 2017/10
Y1 - 2017/10
N2 - 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.
AB - 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.
KW - Bruton tyrosine kinase
KW - IL-1
KW - Muckle-Wells syndrome
KW - NLRP3
KW - Staphylococcus aureus
KW - X-linked agammaglobulinemia
KW - ibrutinib
KW - inflammasome
KW - inflammation
KW - macrophage
UR - http://www.scopus.com/inward/record.url?scp=85019758149&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85019758149&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2017.01.017
DO - 10.1016/j.jaci.2017.01.017
M3 - Article
C2 - 28216434
AN - SCOPUS:85019758149
SN - 0091-6749
VL - 140
SP - 1054-1067.e10
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 4
ER -