期刊
CELLS
卷 9, 期 7, 页码 -出版社
MDPI
DOI: 10.3390/cells9071591
关键词
all-trans retinoic acid; NLRP3 inflammasome; IL-1 beta; signaling; metabolism; human macrophages
类别
资金
- Hungarian National Scientific Research Fund (NKFIH-OTKA Grant) [K131844]
- Faculty of Medicine of the University of Debrecen [1G3DBKD0TUDF 247, 1Q4D BKX5STIP320, 1G3DBKJ0BFTK 247]
- Premium Postdoctoral Fellowship Program of the Hungarian Academy of Sciences
- Hungarian Scientific Research Found [OTKA FK132185]
- Stipendium Hungaricum Scholarship from the Government of Hungary
All-trans retinoic acid (ATRA) is a derivative of vitamin A that has many important biological functions, including the modulation of immune responses. ATRA actions are mediated through the retinoic acid receptor that functions as a nuclear receptor, either regulating gene transcription in the nucleus or modulating signal transduction in the cytoplasm. NLRP3 inflammasome is a multiprotein complex that is activated by a huge variety of stimuli, including pathogen- or danger-related molecules. Activation of the inflammasome is required for the production of IL-1 beta, which drives the inflammatory responses of infectious or non-infectious sterile inflammation. Here, we showed that ATRA prolongs the expression of IL-6 and IL-1 beta following a 2-, 6-, 12-, and 24-h LPS (100ng/mL) activation in human monocyte-derived macrophages. We describe for the first time that ATRA modulates both priming and activation signals required for NLRP3 inflammasome function. ATRA alone induces NLRP3 expression, and enhances LPS-induced expression of NLRP3 and pro-IL-1 beta via the regulation of signal transduction pathways, like NF-kappa B, p38, and ERK. We show that ATRA alleviates the negative feedback loop effect of IL-10 anti-inflammatory cytokine on NLRP3 inflammasome function by inhibiting the Akt-mTOR-STAT3 signaling axis. We also provide evidence that ATRA enhances hexokinase 2 expression, and shifts the metabolism of LPS-activated macrophages toward glycolysis, leading to the activation of NLRP3 inflammasome.
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