التفاصيل البيبلوغرافية
| العنوان: |
Tyrosine kinase inhibitors can activate the NLRP3 inflammasome in myeloid cells through lysosomal damage and cell lysis. |
| المؤلفون: |
Neuwirt, Emilia, Magnani, Giovanni, Ćiković, Tamara, Wöhrle, Svenja, Fischer, Larissa, Kostina, Anna, Flemming, Stephan, Fischenich, Nora J., Saller, Benedikt S., Gorka, Oliver, Renner, Steffen, Agarinis, Claudia, Parker, Christian N., Boettcher, Andreas, Farady, Christopher J., Kesselring, Rebecca, Berlin, Christopher, Backofen, Rolf, Rodriguez-Franco, Marta, Kreutz, Clemens |
| المصدر: |
Science Signaling; 1/17/2023, Vol. 16 Issue 768, p1-16, 16p |
| مصطلحات موضوعية: |
LYSIS, MYELOID cells, PROTEIN-tyrosine kinase inhibitors, LYSOSOMES, NLRP3 protein, CANCER cell motility |
| مستخلص: |
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. Off-target support or sabotage: Tyrosine kinase inhibitors (TKIs) are designed to target the proteins that drive proliferation and motility in cancer cells. However, TKIs have variable efficacy and often have adverse side effects. Neuwirt et al. uncovered a kinase target-independent effect of TKIs in immune cells that may contribute to the drugs' overall effects in patients. In a small-molecule screen for activators of inflammasomes, which mediate the innate immune response, some TKIs induced lysosomal damage and lytic cell death, which activated the inflammasome component NLRP3. These effects were selective to myeloid cells. These TKIs included the clinically approved ABL inhibitor imatinib and the ALK inhibitor crizotinib, as well as those in clinical trials, such as the c-KIT inhibitor masitinib, and the cytokines subsequently released could either support or sabotage clinical outcomes. The findings suggest that the success or failure of some TKIs in patients may be influenced by this "off-target" effect in myeloid cells. —LKF [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
