All-Trans Retinoic Acid Enhances both the Signaling for Priming and the Glycolysis for Activation of NLRP3 Inflammasome in Human Macrophage

Abstract

<jats:p>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.</jats:p>

Nuclear Receptors in the Control of the NLRP3 Inflammasome Pathway

“…Interestingly, human LPS-primed macrophages treated with ATRA exhibit elevated NLRP3 RNA and protein levels associated with an increase in caspase 1 and pro-IL-1β maturation. At the molecular level, ATRA alone induces NLRP3 expression and enhances LPS-induced NRLP3 and IL-1β mRNA levels by upregulating the phosphorylation of I κ B, ERK, and p38 ( 122 ). Therefore, stimulation of GR, MR, PXR, and RAR induces NLRP3 priming.…”

“…Finally, glycolysis and metabolic intermediates were shown to impact NLRP3 activation and ROS production ( 150 ). Interestingly, ATRA treatment induces hexokinase 2 expression in human LPS-primed monocyte-derived macrophages, thus shifting the metabolism of macrophages toward glycolysis and activating the NLRP3 inflammasome ( 122 ). Imbalance of metabolic homeostasis then appears to be directly linked to the NLRP3 inflammasome activity and the innate immune system thus emphasizing the importance of metabolic sensors in the control of inflammatory pathway.…”

An update on the regulatory mechanisms of NLRP3 inflammasome activation

“…All- trans -retinoic acid, a derivative of vitamin A, induces the expression of NLRP3 and pro-IL-1β at the priming step and promotes activation of the NLRP3 inflammasome by inducing human macrophages to undergo glycolysis. 225 Further investigations of nuclear receptor interactions with NLRP3 inflammasome pathway components are likely to provide an explanation for the molecular mechanisms underlying the priming step being regulated in a gene-specific manner.…”

From Maternal Diet to Neurodevelopmental Disorders: A Story of Neuroinflammation

“…Vitamin A through its metabolized active form, retinoic acid, can modulate immune homeostasis by binding to retinoic acid and retinoid receptors, which then acts as and interacts with transcription factors ( Spiegler et al, 2012 ; Oliveira et al, 2018 ). As such, retinoic acid can modulate inflammatory processes—including infiltration of immune cells, production of cytokines [e.g., IL-1β, IL-4, IL-6, IL-10, IL-12, IL-18, interferon (IFN)-γ, transforming growth factor beta (TGF-β), tumor necrosis factor (TNF)-α], and other inflammatory mediators [NFκB, NOD-like receptor family pyrin domain-containing protein 3 (NLRP3)]—in a variety of tissues ( Kang et al, 2000 ; Wang et al, 2007 ; Oliveira et al, 2018 ; Elshal et al, 2019 ; Alatshan et al, 2020 ). Thus, dietary intake of vitamin A can influence inflammatory response.…”