2. Academic Validation
  3. Tyrosine kinase inhibitors can activate the NLRP3 inflammasome in myeloid cells through lysosomal damage and cell lysis

Tyrosine kinase inhibitors can activate the NLRP3 inflammasome in myeloid cells through lysosomal damage and cell lysis

  • Sci Signal. 2023 Jan 17;16(768):eabh1083. doi: 10.1126/scisignal.abh1083.
Emilia Neuwirt 1 2 3,  Giovanni Magnani 4,  Tamara Ćiković 4 5,  Svenja Wöhrle 1 3,  Larissa Fischer 1 3,  Anna Kostina 1,  Stephan Flemming 6,  Nora J Fischenich 1,  Benedikt S Saller 1 3,  Oliver Gorka 1,  Steffen Renner 7,  Claudia Agarinis 7,  Christian N Parker 7,  Andreas Boettcher 7,  Christopher J Farady 7,  Rebecca Kesselring 8 9,  Christopher Berlin 8 9,  Rolf Backofen 2 6,  Marta Rodriguez-Franco 10,  Clemens Kreutz 2 11,  Marco Prinz 1 2 12,  Martina Tholen 13,  Thomas Reinheckel 2 9 13,  Thomas Ott 2 10,  Christina J Groß 2,  Philipp J Jost 14,  Olaf Groß 1 2 12
Affiliations

Affiliations

  • 1 Institute of Neuropathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
  • 2 Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 79104 Freiburg, Germany.
  • 3 Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
  • 4 Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany.
  • 5 Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, 81675 Munich, Germany.
  • 6 Bioinformatics Group, Faculty of Engineering, University of Freiburg, 79110 Freiburg, Germany.
  • 7 Novartis Institutes for BioMedical Research, 4056 Basel, Switzerland.
  • 8 Department for General and Visceral Surgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
  • 9 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) 69120 Heidelberg, Germany.
  • 10 Faculty of Biology, Cell Biology, University of Freiburg, 79104 Freiburg, Germany.
  • 11 Institute of Medical Biometry and Statistics (IMBI), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
  • 12 Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
  • 13 Institute for Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.
  • 14 Division of Clinical Oncology, Department of Medicine, Medical University of Graz, 8036 Graz, Austria.
PMID: 36649377 DOI: 10.1126/scisignal.abh1083
Abstract

Inflammasomes are intracellular protein complexes that promote an inflammatory host defense in response to pathogens and damaged or neoplastic tissues and are implicated in inflammatory disorders and therapeutic-induced toxicity. We investigated the mechanisms of activation for inflammasomes nucleated by NOD-like receptor (NLR) protiens. A screen of a small-molecule library revealed that several tyrosine kinase inhibitors (TKIs)-including those that are clinically approved (such as imatinib and crizotinib) or are in clinical trials (such as masitinib)-activated the NLRP3 inflammasome. Furthermore, imatinib and masitinib caused lysosomal swelling and damage independently of their kinase target, leading to cathepsin-mediated destabilization of myeloid cell membranes and, ultimately, Cell Lysis that was accompanied by potassium (K+) efflux, which activated NLRP3. This effect was specific to primary myeloid cells (such as peripheral blood mononuclear cells and mouse bone marrow-derived dendritic cells) and did not occur in other primary cell types or various cell lines. TKI-induced lytic cell death and NLRP3 activation, but not lysosomal damage, were prevented by stabilizing cell membranes. Our findings reveal a potential immunological off-target of some TKIs that may contribute to their clinical efficacy or to their adverse effects.

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