Thioredoxin-1 attenuates atherosclerosis development through inhibiting NLRP3 inflammasome

Wang, Yu; Ji, Ningfei; Gong, Xinyang; Ni, Shimao; Xu, Lei; Zhang, Hui

doi:10.1007/s12020-020-02389-z

Cited by 18 publications

(16 citation statements)

References 29 publications

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“…Namely, in MO-GMCSF cells, we identified strong enrichment of pathways associated with oxidative signaling consistent with emerging models relating metabolism in driving macrophage state (Cameron et al, 2019;West et al, 2011). We speculate that this interplay between oxidative signaling and metabolic state influence a multitude of macrophage functions, such as bacterial clearance and atherosclerosis, in vivo (Di Gioia et al, 2020;Huang et al, 2018;Wang et al, 2020). We identified and validated several novel markers of macrophage state.…”

Section: Gm-csf Mediates a Durable Switch In Il-10 Productionsupporting

confidence: 77%

GM-CSF differentiation of human monocytes stabilizes macrophage state via oxidative signaling

Itoh

Gunnarsson

Babunovic

et al. 2020

Preprint

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Macrophages are central mediators of immunity that integrate diverse signals derived from differentiation cues, tissue location, and disease. Controlling macrophage state and function is an appealing therapeutic objective across many diseases including cancer, atherosclerosis, and tuberculosis. Despite the growing appreciation for the in vivo complexity of macrophage state, existing in vitro models of human monocyte-derived macrophages have used a limited number of individual perturbations to explore the complex phenotypic space that macrophages can occupy. Here, we leverage a tiered differentiation, activation, and stimulation strategy to generate libraries of in vitro monocyte-derived macrophages and examine the in vitro state space of macrophage function using high-dimensional technologies. Our tiered experimental approach further revealed a striking relationship between GM-CSF differentiation and IL-10 production. Cells that were differentiated with GM-CSF produced very low or undetectable levels of IL-10 independent of activation or stimulation condition. To nominate candidate regulators of this IL-10 response, we leverage unbiased single-cell mRNA sequencing to identify transcriptional networks associated with GM-CSF-derived cells. Using these data, we identify oxidative signaling pathways as upregulated in GM-CSF derived cells and demonstrate that scavenging of oxidative radicals can enhance IL-10 production in these cells. Collectively, these data underscore the complexity of monocyte-derived macrophage state over time and highlight a dominant role for GM-CSF in tuning macrophage inflammatory phenotype, metabolic state, and plasticity.

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Section: Gm-csf Mediates a Durable Switch In Il-10 Productionsupporting

confidence: 77%

GM-CSF differentiation of human monocytes stabilizes macrophage state via oxidative signaling

Itoh

Gunnarsson

Babunovic

et al. 2020

Preprint

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“…In atherosclerosis, macrophages play a central role in the initiation, growth, and final rupture of arterial plaque. Various studies based on different purposes have fully proved the vital role of macrophage inflammasome activation in the pathogenesis of atherosclerosis ( Tang et al, 2019 ; Yin et al, 2019 ; Tian et al, 2020 ; Wang et al, 2020 ). NLRP3 inflammasome activation is considered to be a key catalyst for atherogenesis.…”

Section: Introductionmentioning

confidence: 99%

α1-nAchR-Mediated Signaling Through Lipid Raft Is Required for Nicotine-Induced NLRP3 Inflammasome Activation and Nicotine-Accelerated Atherosclerosis

Fu-jian

Zeng

Liu

et al. 2021

Front. Cell Dev. Biol.

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BackgroundNicotine exerts direct effects on multiple cell types in the cardiovascular system by associating with its high-affinity nicotinic acetylcholine receptors (nAchRs). Lipid raft is a membrane microdomain that recruits various receptors and signaling molecules for coordinating cellular immune response and many others signaling processes. Here, we aim to identify the essential role of lipid raft in mediating nicotine-triggered inflammatory and nicotine-accelerated atherosclerosis, and to figure out the specific receptor of nicotine-induced Nod-like receptor protein 3 (NLRP3) inflammasome activation in macrophage.Methods and ResultsApoE–/– mice were fed with a high-fat diet to build atherosclerosis model. Methyl-β-cyclodextrin was used to interrupt intact lipid raft. We confirmed that nicotine triggered NLRP3 inflammasome activation and induced macrophage migration into atherosclerotic plaque, thus accelerated atherosclerosis in apoE–/– mice fed with a high-fat diet. Mechanically, nicotine increased the expression of α1-nAChR and stimulated the accumulation of α1-nAChR in lipid raft, leading to NLRP3 inflammasome activation in macrophage. Conversely, silencing of α1-nAChR in macrophage sufficiently blocked the pro-inflammasome activation effect of nicotine, indicating that α1-nAChR was the specific receptor for nicotine in triggering NLRP3 inflammasome in macrophage. Furthermore, both the destruction of lipid raft by methyl-β-cyclodextrin and the interference of lipid raft clustering by silencing acid sphingomyelinase reversed nicotine-induced NLRP3 inflammasome activation by reducing the accumulation of α1-nAChR in lipid raft in macrophage, suggesting lipid raft–mediated accumulation of α1-nAChR was the key event in regulating the pro-inflammatory effects of nicotine in macrophage. Importantly, nicotine-induced NLRP3 inflammasome activation and macrophage migration into atherosclerotic plaque were reversed by methyl-β-cyclodextrin, making a significant improvement for atherosclerosis in apoE–/– mice fed with a high-fat diet.Conclusionα1-nAChR-mediated signaling through lipid raft is required for NLRP3 inflammasome activation and pro-atherosclerotic property of nicotine.

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“…Combating NLRP3 inflammasome activation by thioredoxin-1 significantly mitigates ROS-stimulating NLRP3 generation, IL-1β secretion and gets atherosclerosis stunted, unfolding atheroprotective functions. 127 Some other tactics of indirect or direct depressing NLRP3 inflammasome have been demonstrated to block inflammasome activation for diminished IL-1β with selectivity and advantage, embodying small-molecule inhibitors (MCC950, 128 β-hydroxybutyrate, arglabin) and microRNA(microRNA-223, suppressing NLRP3 protein expression), 129 and more inhibitors also had been summarized by Zahid and their colleagues. 130 The new therapeutic strategies inhibiting NLRP3 inflammasome activation are burgeoning.…”

Section: Aiming At Critical Pathological Proceedingmentioning

confidence: 99%

Recent advance in treatment of atherosclerosis: Key targets and plaque-positioned delivery strategies

Liu

Tan

et al. 2022

J Tissue Eng

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Atherosclerosis, a chronic inflammatory disease of vascular wall, is a progressive pathophysiological process with lipids oxidation/depositing initiation and innate/adaptive immune responses. The coordination of multi systems covering oxidative stress, dysfunctional endothelium, diseased lipid uptake, cell apoptosis, thrombotic and pro-inflammatory responding as well as switched SMCs contributes to plaque growth. In this circumstance, inevitably, targeting these processes is considered to be effective for treating atherosclerosis. Arriving, retention and working of payload candidates mediated by targets in lesion direct ultimate therapeutic outcomes. Accumulating a series of scientific studies and clinical practice in the past decades, lesion homing delivery strategies including stent/balloon/nanoparticle-based transportation worked as the potent promotor to ensure a therapeutic effect. The objective of this review is to achieve a very brief summary about the effective therapeutic methods cooperating specifical targets and positioning-delivery strategies in atherosclerosis for better outcomes.

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Thioredoxin-1 attenuates atherosclerosis development through inhibiting NLRP3 inflammasome

Cited by 18 publications

References 29 publications

GM-CSF differentiation of human monocytes stabilizes macrophage state via oxidative signaling

GM-CSF differentiation of human monocytes stabilizes macrophage state via oxidative signaling

α1-nAchR-Mediated Signaling Through Lipid Raft Is Required for Nicotine-Induced NLRP3 Inflammasome Activation and Nicotine-Accelerated Atherosclerosis

Recent advance in treatment of atherosclerosis: Key targets and plaque-positioned delivery strategies

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