TY  - JOUR
AU  - Neuwirt, Emilia
AU  - Magnani, Giovanni
AU  - Ćiković, Tamara
AU  - Wöhrle, Svenja
AU  - Fischer, Larissa
AU  - Kostina, Anna
AU  - Flemming, Stephan
AU  - Fischenich, Nora J
AU  - Saller, Benedikt S
AU  - Gorka, Oliver
AU  - Renner, Steffen
AU  - Agarinis, Claudia
AU  - Parker, Christian N
AU  - Boettcher, Andreas
AU  - Farady, Christopher J
AU  - Kesselring, Rebecca
AU  - Berlin, Christopher
AU  - Backofen, Rolf
AU  - Rodriguez-Franco, Marta
AU  - Kreutz, Clemens
AU  - Prinz, Marco
AU  - Tholen, Martina
AU  - Reinheckel, Thomas
AU  - Ott, Thomas
AU  - Groß, Christina J
AU  - Jost, Philipp J
AU  - Groß, Olaf
TI  - Tyrosine kinase inhibitors can activate the NLRP3 inflammasome in myeloid cells through lysosomal damage and cell lysis.
JO  - Science signaling
VL  - 16
IS  - 768
SN  - 1945-0877
CY  - Washington, DC [u.a.]
PB  - Assoc.
M1  - DKFZ-2023-00110
SP  - eabh1083
PY  - 2023
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:36649377
DO  - DOI:10.1126/scisignal.abh1083
UR  - https://inrepo02.dkfz.de/record/186782
ER  -