Abstract
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-1β, 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-1β 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-1β via the regulation of signal transduction pathways, like NF-κB, 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.
Highlights
IL-1β is a master cytokine that plays an important role in many immunological and physiological processes [1]
To determine whether all-trans retinoic acid (RA) (ATRA) affects proinflammatory cytokine secretion of activated human monocyte-derived macrophages (MΦs), cells were treated with LPS in the absence or presence of ATRA for various time intervals, and cytokine production was measured using the enzyme-linked immunosorbent assay (ELISA) method
LPS treatment results in rapid IL-1β secretion that reaches a peak at 2 h and gradually decreases over time [34]
Summary
IL-1β is a master cytokine that plays an important role in many immunological and physiological processes [1]. It regulates the activation of cells and modulates cytokine production. It has an important role in T helper (Th) cell polarization, connecting innate and adaptive immune responses. The production of IL-1β is tightly regulated by multiprotein complexes called inflammasomes. Cells 2020, 9, 1591 it can be activated by a wide range of stimuli. NLRP3 inflammasome-mediated IL-1β is required to drive an effective inflammatory response in infectious diseases triggered by pathogenic microorganisms. NLRP3 inflammasome-derived IL-1β is the major driver of chronic low-grade sterile inflammation that accompanies conditions, such as metabolic syndromes and aging, endometriosis, and bronchiolitis obliterans syndrome, eventually leading to tissue damage [2,3,4,5]
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