Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Neuwirt, E; Magnani, G; Cikovic, T; Wohrle, S; Fischer, L; Kostina, A; Flemming, S; Fischenich, NJ; Saller, BS; Gorka, O; Renner, S; Agarinis, C; Parker, CN; Boettcher, A; Farady, CJ; Kesselring, R; Berlin, C; Backofen, R; Rodriguez-Franco, M; Kreutz, C; Prinz, M; Tholen, M; Reinheckel, T; Ott, T; Gross, CJ; Jost, PJ; Gross, O.
Tyrosine kinase inhibitors can activate the NLRP3 inflammasome in myeloid cells through lysosomal damage and cell lysis
SCI SIGNAL. 2023; 16(768): eabh1083
Doi: 10.1126/scisignal.abh1083
Web of Science
PubMed
FullText
FullText_MUG
- Co-Autor*innen der Med Uni Graz
- Jost Philipp
- Altmetrics:
- Dimensions Citations:
- Plum Analytics:
- Scite (citation analytics):
- 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) proteins. 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.