Journal Article

DKFZ-2023-00110

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Tyrosine kinase inhibitors can activate the NLRP3 inflammasome in myeloid cells through lysosomal damage and cell lysis.

Neuwirt, E. ; Magnani, G. ; Ćiković, T. ; Wöhrle, S. ; Fischer, L. ; Kostina, A. ; Flemming, S. ; Fischenich, N. J. ; Saller, B. S. ; Gorka, O. ; Renner, S. ; Agarinis, C. ; Parker, C. N. ; Boettcher, A. ; Farady, C. J. ; Kesselring, R.DKFZ* ; Berlin, C.DKFZ* ; Backofen, R. ; Rodriguez-Franco, M. ; Kreutz, C. ; Prinz, M. ; Tholen, M. ; Reinheckel, T.DKFZ* ; Ott, T. ; Groß, C. J. ; Jost, P. J. ; Groß, O.

2023
Assoc. Washington, DC [u.a.]

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Please use a persistent id in citations: 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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Contributing Institute(s):

1. DKTK FR zentral (FR01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2023

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Essential Science Indicators ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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