Genome-wide screen based on 2DG activated NLRP3 inflammasome reveals the priming signal of TLR2/4 to IKKβ but not IKKα.

IF 4.8 2区 医学 Q2 IMMUNOLOGY
International immunopharmacology Pub Date : 2025-01-03 Epub Date: 2024-12-09 DOI:10.1016/j.intimp.2024.113781
Hui Gao, Mengning Sun, Hang Gao, Yi Sun, Wenjuan Chen, Na Dong
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引用次数: 0

Abstract

NLRP3 inflammasome activation is a pivotal area of research in innate immunity, yet the precise priming and activation signal remain unclear. In this study, we demonstrate that glycolysis inhibitor 2-Deoxy-D-glucose (2DG) triggers NLRP3-driven pyroptosis in human leukemia monocyte THP-1 cells by interfering glycosylation rather than glycolysis, which occurs independent of potassium efflux but requires the involvement of glycolysis rate-limiting enzyme PFKP. Using a CRISPR-Cas9 mediated large-scale screen, with 2DG as a new tool for probing NLRP3 activation, we identified that TLR2, rather than TLR4, initiates a rapid and robust priming signal for NLRP3 inflammasome activation. Importantly, both TLR2 and TLR4 depend entirely on MyD88, but not TRIF, for signal transduction. Furthermore, we discovered that TAK1, IKKβ and NEMO, but not IKKα, are essential for the priming signal. Additionally, we observed that deficiency in the linear ubiquitin assembly complex (LUBAC) subunits HOIP and HOIL-1, but not SHARPIN, is sufficient to inhibit 2DG-induced pyroptotic cell death. Collectively, our study reveals some common mechanism in the NLRP3 priming signals, as well as specific mechanisms upstream of NLRP3 triggered by 2DG, and underscores the potential of 2DG as a trigger to facilitate further detailed analysis of the underlying mechanisms of NLRP3 inflammasome activation. One Sentence Summary: Priming signal by IKKβ is essential for NLRP3 activation.

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来源期刊
CiteScore
8.40
自引率
3.60%
发文量
935
审稿时长
53 days
期刊介绍: International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.
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