RT Journal Article
SR Electronic
T1 Tyrosine kinase inhibitors trigger lysosomal damage-associated cell lysis to activate the NLRP3 inflammasome
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.02.19.480941
DO 10.1101/2022.02.19.480941
A1 Emilia Neuwirt
A1 Giovanni Magnani
A1 Tamara Ćiković
A1 Anna Kostina
A1 Svenja Wöhrle
A1 Stephan Flemming
A1 Larissa Fischer
A1 Nora J. Fischenich
A1 Benedikt S. Saller
A1 Oliver Gorka
A1 Steffen Renner
A1 Claudia Agarinis
A1 Christian Parker
A1 Andreas Boettcher
A1 Christopher J. Farady
A1 Rolf Backofen
A1 Marta Rodriguez-Franco
A1 Martina Tholen
A1 Thomas Reinheckel
A1 Thomas Ott
A1 Christina J. Groß
A1 Philipp J. Jost
A1 Olaf Groß
YR 2022
UL http://biorxiv.org/content/early/2022/02/19/2022.02.19.480941.abstract
AB Inflammasomes are intracellular protein complexes that control proteolytic maturation and secretion of inflammatory interleukin-1 (IL-1) family cytokines and are thus important in host defense. While some inflammasomes are activated simply by binding to pathogen-derived molecules, others, including those nucleated by NLRP3 and NLRP1, have more complex activation mechanisms that are not fully understood. We screened a library of small molecules to identify new inflammasome activators that might shed light on activation mechanisms. In addition to validating dipeptidyl peptidase (DPP) inhibitors as NLRP1 activators, we find that clinical tyrosine kinase inhibitors (TKIs) including imatinib and masitinib activate the NLRP3 inflammasome. Mechanistically, these TKIs cause lysosomal swelling and damage, leading to cathepsin-mediated destabilization of myeloid cell membranes and cell lysis. This is accompanied by potassium (K+) efflux, which activates NLRP3. Both lytic cell death and NLRP3 activation but not lysosomal damage induced by TKIs are prevented by the cytoprotectant high molecular weight polyethylene glycol (PEG). Our study establishes a screening method that can be expanded for inflammasome research and immunostimulatory drug development, and provides new insight into immunological off-targets that may contribute to efficacy or adverse effects of TKIs.One Sentence Summary A functional small molecule screen identifies imatinib, masitinib and other tyrosine kinase inhibitors that destabilize myeloid cell lysosomes, leading to cell lysis and K+ efflux-dependent NLRP3 inflammasome activation.Competing Interest StatementS.R., C.A., C.P., A.B., and C.J.F. are employees of Novartis, Basel, Switzerland. P.J.J. has had a consulting or advisory role, received honoraria, research funding, and/or travel/accommodation expenses not related to the present work from: Ariad, Abbvie, Bayer, Boehringer, Novartis, Pfizer, Servier, Roche, BMS and Celgene, Pierre Fabre, Janssen / Johnson&Johnson, MSD.