NLRP3 inflammasome activation, metabolic danger signals, and protein binding partners

Leu, Sy-Ying; Tsang, Yi-Ling; Ho, Li-Chun; Yang, Ching-Chun; Shao, Ai-Ning; Chang, Chia-Yu; Lin, Hui-kuan; Tsai, Pei-Jane; Sung, Junne‐Ming; Tsai, Yau‐Sheng

doi:10.1530/joe-22-0184

Cited by 13 publications

(7 citation statements)

References 85 publications

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“…The NOD-like receptor protein-3 (NLRP3) inflammasome includes a pyrin domain (PYD) at the N-terminus, a central NACHT domain (including seven motifs with a nucleotide adenosine triphosphate/guanosine triphosphate (ATP/GTPase) P-loop and Walker A and B binding sites), and nine leucine-rich repeats (LRR) at the C-terminal Fig. 1 [40]. Although NLRP3 is inactive in its monomeric form, its assembly results in NLRP3 inflammasome formation through interactions with apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD) (ASC) [41].…”

Section: Nlrp3 Inflammasomementioning

confidence: 99%

The interaction of inflammasomes and gut microbiota: novel therapeutic insights

Manshouri,

Seif,

Kamali

et al. 2024

Cell Commun Signal

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Inflammasomes are complex platforms for the cleavage and release of inactivated IL-1β and IL-18 cytokines that trigger inflammatory responses against damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs). Gut microbiota plays a pivotal role in maintaining gut homeostasis. Inflammasome activation needs to be tightly regulated to limit aberrant activation and bystander damage to the host cells. Several types of inflammasomes, including Node-like receptor protein family (e.g., NLRP1, NLRP3, NLRP6, NLRP12, NLRC4), PYHIN family, and pyrin inflammasomes, interact with gut microbiota to maintain gut homeostasis. This review discusses the current understanding of how inflammasomes and microbiota interact, and how this interaction impacts human health. Additionally, we introduce novel biologics and antagonists, such as inhibitors of IL-1β and inflammasomes, as therapeutic strategies for treating gastrointestinal disorders when inflammasomes are dysregulated or the composition of gut microbiota changes.

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Section: Nlrp3 Inflammasomementioning

confidence: 99%

The interaction of inflammasomes and gut microbiota: novel therapeutic insights

Manshouri,

Seif,

Kamali

et al. 2024

Cell Commun Signal

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“…There are two major intracellular ROS sources: mitochondria-derived ROS and NADPH oxidase-derived ROS [39]. Experiments in multiple cell systems show that activation of NLRP3 inflammasomes is independent of NADPH oxidase [40,41]. Therefore, mitochondria-derived ROS are critical for NLRP3 inflammasome activation [42,43].…”

Section: Plos Onementioning

confidence: 99%

“…In addition to oxidative stress associated with mito-ROS, mitochondrial dysfunction (e.g, mtDNA release, defective mitochondrial membrane potential, aberrant mitochondrial dynamics, impaired mitochondrial homeostasis) are also major drivers for the activation of NLRP3 inflammasomes, intensifying the NLRP3 inflammasome-mediated pro-inflammatory responses [25,41,46]. Whether or not olaparib regulates NLRP3 inflammasome activity through mitochondrial dynamics, membrane integrity and homeostasis, and noncanonical pathway such as caspase-11 warrants further investigation.…”

Section: Plos Onementioning

confidence: 99%

Poly-(ADP-ribose) polymerases inhibition by olaparib attenuates activities of the NLRP3 inflammasome and of NF-κB in THP-1 monocytes

Mustafa,

Han,

et al. 2024

PLoS ONE

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Poly-(ADP-ribose) polymerases (PARPs) are a protein family that make ADP-ribose modifications on target genes and proteins. PARP family members contribute to the pathogenesis of chronic inflammatory diseases, including atherosclerosis, in which monocytes/macrophages play important roles. PARP inhibition is protective against atherosclerosis. However, the mechanisms by which PARP inhibition exerts this beneficial effect are not well understood. Here we show that in THP-1 monocytes, inhibition of PARP by olaparib attenuated oxidized low-density lipoprotein (oxLDL)-induced protein expressions of nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing-3 (NLRP3) inflammasome components: NLRP3, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), and caspase-1. Consistent with this effect, olaparib decreased oxLDL-enhanced interleukin (IL)-1β and IL-18 protein expression. Olaparib also decreased the oxLDL-mediated increase in mitochondrial reactive oxygen species. Similar to the effects of the NLRP3 inhibitor, MCC950, olaparib attenuated oxLDL-induced adhesion of monocytes to cultured human umbilical vein endothelial cells and reduced foam cell formation. Furthermore, olaparib attenuated the oxLDL-mediated activation of nuclear factor (NF)-κB through the oxLDL-mediated increase in IκBα phosphorylation and assembly of NF-κB subunits, demonstrated by co-immunoprecipitation of IκBα with RelA/p50 and RelB/p52 subunits. Moreover, PARP inhibition decreased oxLDL-mediated protein expression of a NF-κB target gene, VCAM1, encoding vascular cell adhesion molecule-1. This finding indicates an important role for NF-κB activity in PARP-mediated activation of the NLRP3 inflammasome. Thus, PARP inhibition by olaparib attenuates NF-κB and NLRP3 inflammasome activities, lessening monocyte cell adhesion and macrophage foam cell formation. These inhibitory effects of olaparib on NLRP3 activity potentially protect against atherosclerosis.

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“…The NLRP3 in ammasome is an intracellular receptor that recognizes various microbial patterns, internal danger signals, and external irritants, leading to its assembly and activation 5 . Assembly of the NLRP3 in ammasome leads to caspase 1-dependent release of the pro-in ammatory cytokines IL-1β and IL-18 6,7 , as well as to Gasdermin D-mediated pyroptosis 8 .…”

Section: Introductionmentioning

confidence: 99%

Carvedilol ameliorates experimental atherosclerosis by inhibiting the NLRP3 inflammasome

Xu,

Yan,

et al. 2024

Preprint

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Objective: To investigate the protective effect of carvedilol against atherosclerosis by inhibiting the NLRP3 inflammasome. Methods：In vitro experiments, human umbilical vein endothelial cells(HUVEC) were divided into the control group, ox-LDL group, carvedilol 5μM group, carvedilol 10μM group, and carvedilol 20μM group. The optimal concentration of carvedilol was determined using the CCK-8 method to assess cell proliferation levels and oil red O staining to observe intracellular lipid droplet formation. Subsequently, the cells were further divided into the control group, ox-LDL group, carvedilol 5μM (optimal concentration) group, and MCC950 (inhibitor of NLRP3 Inflammasome) group. The expression levels of intracellular proteins NLRP3, pro-Caspase-1, Caspase1, pro-IL-1β, IL-1β, p65, GSDMD, and N-GSDMD were detected by ELISA, or Western Blotting. Results: Compared to the control group, the ox-LDL group exhibited a significant reduction in cell proliferation level (P<0.05), accompanied by an increase in lipid droplet formation upon induction. In contrast, pretreatment with carvedilol at concentrations of 5μM, 10μM, and 20μM effectively promoted cell proliferation (P<0.05) and inhibited intracellular lipid droplet formation. Notably, the most pronounced effect was observed with carvedilol pretreatment at a concentration of 5μM. Furthermore, compared to the control group, HUVEC cells in the ox-LDL group demonstrated substantial upregulation of NLRP3, pro-Caspase-1, Caspase1, pro-IL-1β, IL-1β, p65 GSDMD and N-GSDMD; however, these markers were downregulated following treatment with carvedilol and MCC950 administration-particularly evident in the carvedilol group. Conclusion: Carvedilol effectively inhibits the progression of atherosclerosisby targeting the NLRP3 inflammasome, thereby providing valuable mechanistic insights into its beneficial effects on atherosclerotic cardiovascular disease.

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NLRP3 inflammasome activation, metabolic danger signals, and protein binding partners

Cited by 13 publications

References 85 publications

The interaction of inflammasomes and gut microbiota: novel therapeutic insights

The interaction of inflammasomes and gut microbiota: novel therapeutic insights

Poly-(ADP-ribose) polymerases inhibition by olaparib attenuates activities of the NLRP3 inflammasome and of NF-κB in THP-1 monocytes

Carvedilol ameliorates experimental atherosclerosis by inhibiting the NLRP3 inflammasome

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