Phytochemicals as Novel Therapeutic Strategies for NLRP3 Inflammasome-Related Neurological, Metabolic, and Inflammatory Diseases

Several lines of evidence point out the relevance of nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome as a pivotal player in the pathophysiology of several neurological and psychiatric diseases (i.e., Parkinson’s disease (PD), Alzheimer’s disease (AD), multiple sclerosis (MS), amyotrophic lateral sclerosis, and major depressive disorder), metabolic disorders (i.e., obesity and type 2 diabetes) and chronic inflammatory diseases (i.e., intestinal inflammation, arthritis, and gout). Intensive research efforts are being made to achieve an integrated view about the pathophysiological role of NLRP3 inflammasome pathways in such disorders. Evidence is also emerging that the pharmacological modulation of NLRP3 inflammasome by phytochemicals could represent a promising molecular target for the therapeutic management of neurological, psychiatric, metabolic, and inflammatory diseases. The present review article has been intended to provide an integrated and critical overview of the available clinical and experimental evidence about the role of NLRP3 inflammasome in the pathophysiology of neurological, psychiatric, metabolic, and inflammatory diseases, including PD, AD, MS, depression, obesity, type 2 diabetes, arthritis, and intestinal inflammation. Special attention has been paid to highlight and critically discuss current scientific evidence on the effects of phytochemicals on NLRP3 inflammasome pathways and their potential in counteracting central neuroinflammation, metabolic alterations, and immune/inflammatory responses in such diseases.

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Nutrients and Immunometabolism: Role of Macrophage NLRP3

Journal of Nutrition ◽

10.1093/jn/nxaa085 ◽

2020 ◽

Vol 150 (7) ◽

pp. 1693-1704

Author(s):

Kate J Claycombe-Larson ◽

Travis Alvine ◽

Dayong Wu ◽

Nishan S Kalupahana ◽

Naima Moustaid-Moussa ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Tissue Cell ◽

Cell Functions ◽

Pyrin Domain ◽

Increased Risk ◽

Vital Cell ◽

Cell Type Specific ◽

Specific Regulation

ABSTRACT Inflammation is largely mediated by immune cells responding to invading pathogens, whereas metabolism is oriented toward producing usable energy for vital cell functions. Immunometabolic alterations are considered key determinants of chronic inflammation, which leads to the development of chronic diseases. Studies have demonstrated that macrophages and the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome are activated in key metabolic tissues to contribute to increased risk for type 2 diabetes mellitus, Alzheimer disease, and liver diseases. Thus, understanding the tissue-/cell-type–specific regulation of the NLRP3 inflammasome is crucial for developing intervention strategies. Currently, most of the nutrients and bioactive compounds tested to determine their inflammation-reducing effects are limited to animal models. Future studies need to address how dietary compounds regulate immune and metabolic cell reprograming in humans.

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NLRP3 inflammasome is involved in uterine activation for labor at term and preterm

Reproduction ◽

10.1530/rep-21-0047 ◽

2021 ◽

Vol 162 (6) ◽

pp. 449-460

Author(s):

Zixi Chen ◽

Yali Shan ◽

Xingji You ◽

Hang Gu ◽

Chen Xu ◽

...

Keyword(s):

Mouse Model ◽

Nlrp3 Inflammasome ◽

Inflammatory Diseases ◽

Critical Role ◽

Inflammasome Activation ◽

Pyrin Domain ◽

Nlrp3 Inflammasome Activation ◽

Pregnant Mice ◽

Labor Onset

The nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome plays a critical role in various inflammatory diseases. We sought to investigate the role of NLRP3 inflammasome in uterine activation for labor at term and preterm. We found that NLRP3 inflammasome was activated in the myometrium tissues obtained from the pregnant women undergoing labor at term (TL) compared with those not undergoing labor (TNL) at term. NLRP3 inflammasome was also activated in amnion and chorion-deciduas in TL and preterm labor (PTL) groups. In the mouse model, uterine NLRP3 inflammasome and nuclear factor kappaB (NF-κB) were activated toward term and during labor. Treatment of pregnant mice with lipopolysaccharide (LPS) and RU38486 induced preterm birth (PTB) and also promoted uterine NLRP3 inflammasome and NF-κB activation. Treatment of pregnant mice with NLRP3 inflammasome inhibitor BAY11-7082 and MCC950 delayed the onset of labor and suppressed NLRP3 inflammasome and NF-κB activation in uterus. MCC950 postponed labor onset of the mice with LPS and RU38486 treatment and inhibited NLRP3 inflammasome activation in uterus. Our data provide the evidence that NLRP3 inflammasome is involved in uterine activation for labor onset in term and PTB in humans and mouse model.

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Genetic variation in CARD8, a gene coding for an NLRP3 inflammasome-associated protein, alters the genetic risk for diabetic nephropathy in the context of type 2 diabetes mellitus

Diabetes and Vascular Disease Research ◽

10.1177/1479164120970892 ◽

2020 ◽

Vol 17 (6) ◽

pp. 147916412097089

Author(s):

Fotis Tsetsos ◽

Athanasios Roumeliotis ◽

Xanthippi Tsekmekidou ◽

Sophia Alexouda ◽

Stefanos Roumeliotis ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Diabetic Nephropathy ◽

Nlrp3 Inflammasome ◽

Inflammatory Responses ◽

Genes Encoding ◽

Stage Renal Disease ◽

End Stage

Background: Approximately one third of type 2 diabetes mellitus (T2DM) cases present with diabetic nephropathy (DN), the leading cause of end-stage renal disease. Inflammation plays an important role in T2DM disease and DN pathogenesis. NLRP3 inflammasomes are complexes that regulate interleukin-1B (IL-1B) and IL-18 secretion, both involved in inflammatory responses. Activation of NLRP3 is associated with DN onset and progression. Here, we explore whether DN is associated with variants in genes encoding key members of the NLRP3 inflammasome pathway. Methods: Using genome-wide association data, we performed a pilot case-control association study, between 101 DN-T2DM and 185 non-DN-T2DM cases from the Hellenic population across six NLRP3 inflammasome pathway genes. Results: Three common CARD8 variants confer decreased risk for DN, namely rs11665831 (OR = 0.62, p = 0.016), rs11083925 (OR = 0.65, p = 0.021), and rs2043211 (OR = 0.66, p = 0.026), independent of sex or co-inheritance with an IL-1B variant. Conclusion: CARD8 acts as an NLRP3, NF-κB and caspase-1 inhibitor; perhaps, alterations in the cross-talk between CARD8, NF-κB, and NLRP3, which could affect the pro-inflammatory environment in T2DM, render diabetic carriers of certain common CARD8 variants potentially less likely to develop T2DM-related pro-inflammatory responses followed by DN. These preliminary, yet novel, observations will require validation in larger cohorts from several ethnic groups.

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Interleukin-22 Might Act as a Double-Edged Sword in Type 2 Diabetes and Coronary Artery Disease

Mediators of Inflammation ◽

10.1155/2016/8254797 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 15

Author(s):

Fangchen Gong ◽

Jin Wu ◽

Ping Zhou ◽

Mengyao Zhang ◽

Jingning Liu ◽

...

Keyword(s):

Type 2 Diabetes ◽

Coronary Artery Disease ◽

Endothelial Cells ◽

Coronary Artery ◽

Inflammatory Diseases ◽

Elevated Serum ◽

Low Grade ◽

Artery Disease

Type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) are both characterized by chronic low-grade inflammation. The role of Th17 and its related cytokines in T2DM and CAD is unclear. Here we investigated the serum levels of five Th17-related cytokines (IL-17, IL-22, MIP-3α, IL-9, and IL-27) in T2DM, CAD, and T2DM-CAD comorbidity patients. IL-22 was found to be elevated in all three conditions. Elevated serum IL-22 was independently associated with the incidence of T2DM and CAD. Conversely, IL-22 was found to protect endothelial cells from glucose- and lysophosphatidylcholine- (LPC-) induced injury, and IL-22R1 expression on endothelial cells was increased upon treatment with high glucose and LPC. Blocking of IL-22R1 with IL-22R1 antibody diminished the protective role of IL-22. Our results suggest that IL-22 functions as a double-edged sword in T2DM and CAD and that IL-22 may be used in the treatment of chronic inflammatory diseases such as T2DM and CAD.

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NLRP3 inflammasome as a key driver of vascular disease

Cardiovascular Research ◽

10.1093/cvr/cvab010 ◽

2021 ◽

Author(s):

Masafumi Takahashi

Keyword(s):

Nlrp3 Inflammasome ◽

Inflammatory Diseases ◽

Vascular Diseases ◽

Diverse Range ◽

Pyrin Domain ◽

Current State ◽

Key Driver ◽

Receptor Family ◽

Oligomerization Domain

Abstract Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) is an intracellular innate immune receptor that recognizes a diverse range of stimuli derived from pathogens, damaged or dead cells, and irritants. NLRP3 activation causes the assembly of a large multiprotein complex termed the NLRP3 inflammasome, and leads to the secretion of bioactive interleukin (IL)-1β and IL-18 as well as the induction of inflammatory cell death termed pyroptosis. Accumulating evidence indicates that NLRP3 inflammasome plays a key role in the pathogenesis of sterile inflammatory diseases, including atherosclerosis and other vascular diseases. Indeed, the results of the Canakinumab Anti-inflammatory Thrombosis Outcome Study trial demonstrated that IL-1β-mediated inflammation plays an important role in atherothrombotic events and suggested that NLRP3 inflammasome is a key driver of atherosclerosis. In this review, we will summarize the current state of knowledge regarding the role of NLRP3 inflammasome in vascular diseases, in particular in atherosclerosis, vascular injury, aortic aneurysm, and Kawasaki disease vasculitis, and discuss NLRP3 inflammasome as a therapeutic target for these disorders.

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NLRP3 Inflammasome at the Interface of Inflammation, Endothelial Dysfunction, and Type 2 Diabetes

Cells ◽

10.3390/cells10020314 ◽

2021 ◽

Vol 10 (2) ◽

pp. 314

Author(s):

Ilona M. Gora ◽

Anna Ciechanowska ◽

Piotr Ladyzynski

Keyword(s):

Type 2 Diabetes ◽

Endothelial Dysfunction ◽

Inflammatory Cytokines ◽

Nlrp3 Inflammasome ◽

Inflammatory Diseases ◽

Vascular Complications ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation ◽

Pro Inflammatory Cytokines

Type 2 diabetes mellitus (T2DM), accounting for 90–95% cases of diabetes, is characterized by chronic inflammation. The mechanisms that control inflammation activation in T2DM are largely unexplored. Inflammasomes represent significant sensors mediating innate immune responses. The aim of this work is to present a review of links between the NLRP3 inflammasome, endothelial dysfunction, and T2DM. The NLRP3 inflammasome activates caspase-1, which leads to the maturation of pro-inflammatory cytokines interleukin 1β and interleukin 18. In this review, we characterize the structure and functions of NLRP3 inflammasome as well as the most important mechanisms and molecules engaged in its activation. We present evidence of the importance of the endothelial dysfunction as the first key step to activating the inflammasome, which suggests that suppressing the NLRP3 inflammasome could be a new approach in depletion hyperglycemic toxicity and in averting the onset of vascular complications in T2DM. We also demonstrate reports showing that the expression of a few microRNAs that are also known to be involved in either NLRP3 inflammasome activation or endothelial dysfunction is deregulated in T2DM. Collectively, this evidence suggests that T2DM is an inflammatory disease stimulated by pro-inflammatory cytokines. Finally, studies revealing the role of glucose concentration in the activation of NLRP3 inflammasome are analyzed. The more that is known about inflammasomes, the higher the chances to create new, effective therapies for patients suffering from inflammatory diseases. This may offer potential novel therapeutic perspectives in T2DM prevention and treatment.

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Novel therapeutic strategies for cardiorenal protection in patients with type 2 diabetes and chronic kidney disease

Current Vascular Pharmacology ◽

10.2174/1570161119666211029111428 ◽

2021 ◽

Vol 19 ◽

Author(s):

Panagiotis I. Georgianos ◽

Stefanos Roumeliotis ◽

Theodoros Eleftheriadis ◽

Vassilios Liakopoulos

Keyword(s):

Type 2 Diabetes ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Early Stage ◽

High Risk Population ◽

Mineralocorticoid Receptor Antagonist ◽

Novel Therapeutic Strategies ◽

End Stage

: Type 2 diabetes mellitus (T2DM) is the leading cause of end-stage kidney disease (ESKD) worldwide [1]. The development of chronic kidney disease (CKD) in patients with T2DM substantially increases their risk for cardiovascular (CV) morbidity and mortality [2]. In fact, when T2DM and early-stage CKD co-exist, the risk for CV death is several times higher than the risk for progression to ESKD [3]. Therefore, there is a need for the development of novel therapies to improve CV and kidney failure outcomes in this high-risk population. In this brief perspective, we explore the role of sodium-glucose co-transporter type-2 (SGLT-2) inhibitors and the nonsteroidal mineralocorticoid-receptor-antagonist (MRA) finerenone, in the management of diabetic kidney disease (DKD).

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Metaflammation, NLRP3 Inflammasome Obesity and Metabolic Disease

The Indonesian Biomedical Journal ◽

10.18585/inabj.v3i3.148 ◽

2011 ◽

Vol 3 (3) ◽

pp. 168

Author(s):

Anna Meiliana ◽

Andi Wijaya

Keyword(s):

Metabolic Disease ◽

Type 2 Diabetes ◽

Nlrp3 Inflammasome ◽

Metabolic Diseases ◽

Inflammatory Responses ◽

Metabolic Stress ◽

Nutrient Sensing ◽

Low Grade ◽

Wide Range

BACKGROUND: Increasing prevalence of obesity gives rise to many problems associated with multiple morbidities, such as diabetes, hypertension, heart disease, sleep apnea and cancer. The mechanism of obesity is very complex, thus its link to various disease is poorly understood. This review highlights important concepts in our understanding of the pathogenesis of obesity and related complications.CONTENT: Many studies have tried to explore the exciting and puzzling links between metabolic homeostasis and inflammatory responses. A form of subclinical, low-grade systemic inflammation is known to be associated with both obesity and chronic disease. This, later called as "metaflammation", refers to metabolically triggered inflammation. The nutrient-sensing pathway and the immune response coordination are facilitated by these molecular sites in order to maintain homeostasis under diverse metabolic and immune conditions. Recent studies have found that the NLRP3 inflammasome during metabolic stress forms a tie linking TXNIP, oxidative stress, and IL-1β production. This provides new opportunities for research and therapy for the disease often described as the next global pandemic: type 2 diabetes mellitus (T2DM).SUMMARY: The crucial role of metaflammation in many complications of obesity shown by the unexpected overlap between inflammatory and metabolic sensors and their downstream tissue responses. Then great interest arose to explore the pathways that integrate nutrient and pathogen sensing, give more understanding in the mechanisms of insulin resistance type 2 diabetes, and other chronic metabolic pathologies. A family of intracellular sensors called NLR family is a critical component of the innate immune system. They can form multiprotein complexes, called inflammasome which is capable of responding to a wide range of stimuli including both microbial and self molecules by activating the cysteine protease caspase-1, leading to processing and secretion of the proinflammatory cytokines IL-1β and IL-18, which play crucial roles in host defense. Inflammasome dysregulation has been linked to some autoinflammatory and metabolic diseases. These provide opportunities to continue to improve our understanding of the nature of metaflammation in the hope of modifying it to prevent and treat diseasese.KEYWORDS: Inflammation, metaflammation, inflammasome, metabolic disease, obesity

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