The NLRP3 Inflammasome as a Novel Player of the Intercellular Crosstalk in Metabolic Disorders

The combination of obesity and type 2 diabetes is a serious health problem, which is projected to afflict 300 million people worldwide by 2020. Both clinical and translational laboratory studies have demonstrated that chronic inflammation is associated with obesity and obesity-related conditions such as insulin resistance. However, the precise etiopathogenetic mechanisms linking obesity to diabetes remain to be elucidated, and the pathways that mediate this phenomenon are not fully characterized. One of the most recently identified signaling pathways, whose activation seems to affect many metabolic disorders, is the “inflammasome,” a multiprotein complex composed of NLRP3 (nucleotide-binding domain and leucine-rich repeat protein 3), ASC (apoptosis-associated speck-like protein containing a CARD), and procaspase-1. NLRP3 inflammasome activation leads to the processing and secretion of the proinflammatory cytokines interleukin- (IL-) 1βand IL-18. The goal of this paper is to review new insights on the effects of the NLRP3 inflammasome activation in the complex mechanisms of crosstalk between different organs, for a better understanding of the role of chronic inflammation in metabolic disease pathogenesis. We will provide here a perspective on the current research on NLRP3 inflammasome, which may represent an innovative therapeutic target to reverse the detrimental metabolic consequences of the metabolic inflammation.

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Inhibiting the NLRP3 Inflammasome Activation with MCC950 Ameliorates Diabetic Encephalopathy in db/db Mice

Molecules ◽

10.3390/molecules23030522 ◽

2018 ◽

Vol 23 (3) ◽

pp. 522 ◽

Cited By ~ 27

Author(s):

Yadong Zhai ◽

Xiangbao Meng ◽

Tianyuan Ye ◽

Weijie Xie ◽

Guibo Sun ◽

...

Keyword(s):

Cognitive Dysfunction ◽

Nlrp3 Inflammasome ◽

Cognitive Disorders ◽

Anxiety And Depression ◽

Inflammasome Activation ◽

Diabetic Encephalopathy ◽

Caspase 1 ◽

Nlrp3 Inflammasome Activation

Diabetes is associated with a high risk of developing cognitive dysfunction and neuropsychiatric disabilities, and these disease symptomsare termed diabetic encephalopathy (DEP). Inflammation is involved in the development of DEP. The cleavage and maturation of the proinflammatory cytokine interleukin (IL)-1β is regulated by the NLRP3 inflammasome. Obese and type 2 diabetic db/db mice show anxiety- and depression-like behaviors and cognitive disorders associated with hippocampal inflammation. The purpose of this study was to explore the role of NLRP3 inflammasome in DEP. Results showed that expression levels of inflammasome components including NLRP3, apoptosis-associated speck-like protein (ASC), and caspase-1, as well as IL-1β in the hippocampus of diabetic db/db mice were higher than those of non-diabetic db/m mice. Treatment of db/db mice with NLRP3 inflammasome inhibitor MCC950 ameliorated anxiety- and depression-like behaviors as well as cognitive dysfunction, and reversed increased NLRP3, ASC, and IL-1βexpression levels and caspase-1 activity in hippocampus. Moreover, MCC950 treatment significantly improved insulin sensitivity in db/db mice. These results demonstrate that inhibition of NLRP3 inflammasome activation may prove to be a potential therapeutic approach for DEP treatment.

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Monocytes from patients with rheumatoid arthritis and type 2 diabetes mellitus display an increased production of interleukin (IL)-1β via the nucleotide-binding domain and leucine-rich repeat containing family pyrin 3(NLRP3)-inflammasome activation: a pos

Clinical & Experimental Immunology ◽

10.1111/cei.12667 ◽

2015 ◽

Vol 182 (1) ◽

pp. 35-44 ◽

Cited By ~ 56

Author(s):

P. Ruscitti ◽

P. Cipriani ◽

P. Di Benedetto ◽

V. Liakouli ◽

O. Berardicurti ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Leucine Rich Repeat ◽

Nucleotide Binding Domain ◽

Nlrp3 Inflammasome Activation

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Vitamin D and the NLRP3 Inflammasome

Applied Sciences ◽

10.3390/app10238462 ◽

2020 ◽

Vol 10 (23) ◽

pp. 8462

Author(s):

Matthew Tunbridge ◽

Pedro Henrique França Gois

Keyword(s):

Vitamin D ◽

Nlrp3 Inflammasome ◽

Clinical Evidence ◽

The Body ◽

Receptor Protein ◽

Inflammasome Activation ◽

Nucleotide Binding Domain ◽

Nlrp3 Inflammasome Activation ◽

Improved Outcomes

Vitamin D (VD) is a steroid hormone classically known for its key role in maintaining calcium homeostasis in the body. VD also has important immunomodulatory functions. This review explores evidence for a role of VD in attenuating the activation of the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome. Dysregulated and inappropriate NLRP3 inflammasome activation occurs in a range of human diseases, including autoinflammatory disorders, metabolic disorders, and infections. VD appears to mediate its effects by binding of the VD receptor (VDR) to the sensor protein NLRP3, inhibiting deubiquitination and downstream inflammasome assembly. Some early clinical evidence suggests improved outcomes in inflammasome-mediated disorders when VD-deficient patients are treated with supplementation therapy.

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Contribution of Autophagy-Notch1-Mediated NLRP3 Inflammasome Activation to Chronic Inflammation and Fibrosis in Keloid Fibroblasts

International Journal of Molecular Sciences ◽

10.3390/ijms21218050 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8050

Author(s):

Seongju Lee ◽

Sun Kyeon Kim ◽

Hyungsun Park ◽

Yu Jin Lee ◽

Song Hee Park ◽

...

Keyword(s):

Notch Signaling ◽

Chronic Inflammation ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Myofibroblast Differentiation ◽

Expression Levels ◽

Notch1 Signaling ◽

Nlrp3 Inflammasome Activation ◽

Keloid Fibroblasts

Keloid is a representative chronic fibroproliferative condition that occurs after tissue injury. Emerging evidence showed that activation of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome is involved in the pro-inflammatory response in injured tissues. However, the role of NLRP3 inflammasome in keloid progression remains unclear. Notch signaling, which activates NLRP3 inflammasome, is known to contribute to scar formation in keloid, but the cause of enhanced Notch signaling in keloid is not clear. We sought to investigate whether autophagy regulates Notch1 signaling in keloid fibroblasts and determine whether Notch1 signaling might regulate NLRP3 inflammasomes and myofibroblast differentiation. An in vitro model of keloid was established by culturing primary keloid fibroblasts from patients. Expression levels of Notch1, NLRP3 inflammasome proteins, pro-inflammatory cytokines, and myofibroblast markers in keloid fibroblasts were examined and compared with those in normal fibroblasts. Autophagy known to mediate Notch1 degradation was also monitored in fibroblasts. Small interfering RNA (siRNA) targeting Notch1 was used to transfect keloid fibroblasts to further examine the role of Notch signaling in NLRP3 inflammasome activation. Expression levels of Notch1 and NLRP3 inflammasome in keloid fibroblasts increased compared to those in normal fibroblasts. Such increases were accompanied by increased LC3 levels and reduced autophagic flux. Notch1 silencing in keloid fibroblasts by siRNA transfection significantly suppressed increased levels of overall NLRP3 inflammasome complex proteins, NF-kB, and α-smooth muscle actin. Autophagy induction by rapamycin treatment in keloid fibroblasts effectively suppressed expression levels of Notch1 and NLRP3 inflammasome proteins. Decreased autophagy activity in keloid can result in Notch1-mediated myofibroblast activation and NLRP3 inflammasome signaling activation which is critical for chronic inflammation. Collectively, these results identify Notch1 as a novel activator of NLRP3 inflammasome signaling leading to chronic tissue damage and myofibroblast differentiation in keloid progression.

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Faculty Opinions recommendation of The role of lysosomal cysteine cathepsins in NLRP3 inflammasome activation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.735165969.793559816 ◽

2019 ◽

Author(s):

Paras Anand

Keyword(s):

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Cysteine Cathepsins ◽

Nlrp3 Inflammasome Activation

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Sendai Virus V Protein Inhibits the Secretion of Interleukin-1β by Preventing NLRP3 Inflammasome Assembly

Journal of Virology ◽

10.1128/jvi.00842-18 ◽

2018 ◽

Vol 92 (19) ◽

Cited By ~ 7

Author(s):

Takayuki Komatsu ◽

Yukie Tanaka ◽

Yoshinori Kitagawa ◽

Naoki Koide ◽

Yoshikazu Naiki ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Sendai Virus ◽

Nipah Virus ◽

Innate Immune ◽

Parainfluenza Virus ◽

Inflammasome Activation ◽

V Protein ◽

Nlrp3 Inflammasome Activation ◽

Human Parainfluenza Virus

ABSTRACT Inflammasomes play a key role in host innate immune responses to viral infection by caspase-1 (Casp-1) activation to facilitate interleukin-1β (IL-1β) secretion, which contributes to the host antiviral defense. The NLRP3 inflammasome consists of the cytoplasmic sensor molecule NLRP3, adaptor protein ASC, and effector protein pro-caspase-1 (pro-Casp-1). NLRP3 and ASC promote pro-Casp-1 cleavage, leading to IL-1β maturation and secretion. However, as a countermeasure, viral pathogens have evolved virulence factors to antagonize inflammasome pathways. Here we report that V gene knockout Sendai virus [SeV V(−)] induced markedly greater amounts of IL-1β than wild-type SeV in infected THP1 macrophages. Deficiency of NLRP3 in cells inhibited SeV V(−)-induced IL-1β secretion, indicating an essential role for NLRP3 in SeV V(−)-induced IL-1β activation. Moreover, SeV V protein inhibited the assembly of NLRP3 inflammasomes, including NLRP3-dependent ASC oligomerization, NLRP3-ASC association, NLRP3 self-oligomerization, and intermolecular interactions between NLRP3 molecules. Furthermore, a high correlation between the NLRP3-binding capacity of V protein and the ability to block inflammasome complex assembly was observed. Therefore, SeV V protein likely inhibits NLRP3 self-oligomerization by interacting with NLRP3 and inhibiting subsequent recruitment of ASC to block NLRP3-dependent ASC oligomerization, in turn blocking full activation of the NLRP3 inflammasome and thus blocking IL-1β secretion. Notably, the inhibitory action of SeV V protein on NLRP3 inflammasome activation is shared by other paramyxovirus V proteins, such as Nipah virus and human parainfluenza virus type 2. We thus reveal a mechanism by which paramyxovirus inhibits inflammatory responses by inhibiting NLRP3 inflammasome complex assembly and IL-1β activation. IMPORTANCE The present study demonstrates that the V protein of SeV, Nipah virus, and human parainfluenza virus type 2 interacts with NLRP3 to inhibit NLRP3 inflammasome activation, potentially suggesting a novel strategy by which viruses evade the host innate immune response. As all members of the Paramyxovirinae subfamily carry similar V genes, this new finding may also lead to identification of novel therapeutic targets for paramyxovirus infection and related diseases.

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NLRP3 Inflammasome Activation in Adipose Tissues and Its Implications on Metabolic Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms21114184 ◽

2020 ◽

Vol 21 (11) ◽

pp. 4184 ◽

Cited By ~ 1

Author(s):

Kelvin Ka-Lok Wu ◽

Samson Wing-Ming Cheung ◽

Kenneth King-Yip Cheng

Keyword(s):

Adipose Tissue ◽

Nlrp3 Inflammasome ◽

Metabolic Disorders ◽

Immune Cell ◽

Diabetic Patients ◽

Inflammasome Activation ◽

Low Grade ◽

Adipose Tissues ◽

Adipose Tissue Dysfunction ◽

Nlrp3 Inflammasome Activation

Adipose tissue is an active endocrine and immune organ that controls systemic immunometabolism via multiple pathways. Diverse immune cell populations reside in adipose tissue, and their composition and immune responses vary with nutritional and environmental conditions. Adipose tissue dysfunction, characterized by sterile low-grade chronic inflammation and excessive immune cell infiltration, is a hallmark of obesity, as well as an important link to cardiometabolic diseases. Amongst the pro-inflammatory factors secreted by the dysfunctional adipose tissue, interleukin (IL)-1β, induced by the NLR family pyrin domain-containing 3 (NLRP3) inflammasome, not only impairs peripheral insulin sensitivity, but it also interferes with the endocrine and immune functions of adipose tissue in a paracrine manner. Human studies indicated that NLRP3 activity in adipose tissues positively correlates with obesity and its metabolic complications, and treatment with the IL-1β antibody improves glycaemia control in type 2 diabetic patients. In mouse models, genetic or pharmacological inhibition of NLRP3 activation pathways or IL-1β prevents adipose tissue dysfunction, including inflammation, fibrosis, defective lipid handling and adipogenesis, which in turn alleviates obesity and its related metabolic disorders. In this review, we summarize both the negative and positive regulators of NLRP3 inflammasome activation, and its pathophysiological consequences on immunometabolism. We also discuss the potential therapeutic approaches to targeting adipose tissue inflammasome for the treatment of obesity and its related metabolic disorders.

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The Roles of Endoplasmic Reticulum in NLRP3 Inflammasome Activation

Cells ◽

10.3390/cells9051219 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1219 ◽

Cited By ~ 3

Author(s):

Yang Zhou ◽

Zhizi Tong ◽

Songhong Jiang ◽

Wenyan Zheng ◽

Jianjun Zhao ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Nlrp3 Inflammasome ◽

Critical Role ◽

Immune Defense ◽

Inflammasome Activation ◽

Nucleotide Binding Domain ◽

Cholesterol Trafficking ◽

Pyrin Domain ◽

Nlrp3 Inflammasome Activation ◽

Molecular Patterns

The NLRP3 (nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3) inflammasome senses pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), and activates caspase-1, which provokes release of proinflammatory cytokines such as interleukin-1β (IL-1β) and IL-18 as well as pyroptosis to engage in innate immune defense. The endoplasmic reticulum (ER) is a large and dynamic endomembrane compartment, critical to cellular function of organelle networks. Recent studies have unveiled the pivotal roles of the ER in NLRP3 inflammasome activation. ER–mitochondria contact sites provide a location for NLRP3 activation, its association with ligands released from or residing in mitochondria, and rapid Ca2+ mobilization from ER stores to mitochondria. ER-stress signaling plays a critical role in NLRP3 inflammasome activation. Lipid perturbation and cholesterol trafficking to the ER activate the NLRP3 inflammasome. These findings emphasize the importance of the ER in initiation and regulation of the NLRP3 inflammasome.

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