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

Autor: Neuwirt E; Institute of Neuropathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 79104 Freiburg, Germany.; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany., Magnani G; Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany., Ćiković T; Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany.; Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, 81675 Munich, Germany., Wöhrle S; Institute of Neuropathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany., Fischer L; Institute of Neuropathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany., Kostina A; Institute of Neuropathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany., Flemming S; Bioinformatics Group, Faculty of Engineering, University of Freiburg, 79110 Freiburg, Germany., Fischenich NJ; Institute of Neuropathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany., Saller BS; Institute of Neuropathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany., Gorka O; Institute of Neuropathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany., Renner S; Novartis Institutes for BioMedical Research, 4056 Basel, Switzerland., Agarinis C; Novartis Institutes for BioMedical Research, 4056 Basel, Switzerland., Parker CN; Novartis Institutes for BioMedical Research, 4056 Basel, Switzerland., Boettcher A; Novartis Institutes for BioMedical Research, 4056 Basel, Switzerland., Farady CJ; Novartis Institutes for BioMedical Research, 4056 Basel, Switzerland., Kesselring R; Department for General and Visceral Surgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) 69120 Heidelberg, Germany., Berlin C; Department for General and Visceral Surgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) 69120 Heidelberg, Germany., Backofen R; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 79104 Freiburg, Germany.; Bioinformatics Group, Faculty of Engineering, University of Freiburg, 79110 Freiburg, Germany., Rodriguez-Franco M; Faculty of Biology, Cell Biology, University of Freiburg, 79104 Freiburg, Germany., Kreutz C; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 79104 Freiburg, Germany.; Institute of Medical Biometry and Statistics (IMBI), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany., Prinz M; Institute of Neuropathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 79104 Freiburg, Germany.; Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany., Tholen M; Institute for Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany., Reinheckel T; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 79104 Freiburg, Germany.; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) 69120 Heidelberg, Germany.; Institute for Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany., Ott T; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 79104 Freiburg, Germany.; Faculty of Biology, Cell Biology, University of Freiburg, 79104 Freiburg, Germany., Groß CJ; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 79104 Freiburg, Germany., Jost PJ; Division of Clinical Oncology, Department of Medicine, Medical University of Graz, 8036 Graz, Austria., Groß O; Institute of Neuropathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 79104 Freiburg, Germany.; Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
Jazyk: angličtina
Zdroj: Science signaling [Sci Signal] 2023 Jan 17; Vol. 16 (768), pp. eabh1083. Date of Electronic Publication: 2023 Jan 17.
DOI: 10.1126/scisignal.abh1083
Abstrakt: 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.
Databáze: MEDLINE
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