scholarly journals The Roles of the NLRP3 Inflammasome in Neurodegenerative and Metabolic Diseases and in Relevant Advanced Therapeutic Interventions

Genes ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 131 ◽  
Author(s):  
Rameez Hassan Pirzada ◽  
Nasir Javaid ◽  
Sangdun Choi
Keyword(s):  
Nlrp3 Inflammasome ◽  
Metabolic Diseases ◽  
Drug Research ◽  
Innate Immune ◽  
Therapeutic Interventions ◽  
Interleukin 18 ◽  
Pyrin Domain ◽  
Nlrp3 Inflammasomes ◽  
Oligomerization Domain

Inflammasomes are intracellular multiprotein complexes in the cytoplasm that regulate inflammation activation in the innate immune system in response to pathogens and to host self-derived molecules. Recent advances greatly improved our understanding of the activation of nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasomes at the molecular level. The NLRP3 belongs to the subfamily of NLRP which activates caspase 1, thus causing the production of proinflammatory cytokines (interleukin 1β and interleukin 18) and pyroptosis. This inflammasome is involved in multiple neurodegenerative and metabolic disorders including Alzheimer’s disease, multiple sclerosis, type 2 diabetes mellitus, and gout. Therefore, therapeutic targeting to the NLRP3 inflammasome complex is a promising way to treat these diseases. Recent research advances paved the way toward drug research and development using a variety of machine learning-based and artificial intelligence-based approaches. These state-of-the-art approaches will lead to the discovery of better drugs after the training of such a system.

scholarly journals Walking down Skeletal Muscle Lane: From Inflammasome to Disease

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3023
Author(s):  
Nicolas Dubuisson ◽  
Romain Versele ◽  
María A. Davis-López de Carrizosa ◽  
Camille M. Selvais ◽  
Sonia M. Brichard ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Nlrp3 Inflammasome ◽  
Innate Immune System ◽  
Current Knowledge ◽  
Innate Immune ◽  
Leucine Rich Repeat ◽  
Muscle Disorders ◽  
Pyrin Domain ◽  
Cardiac Muscles ◽  
Oligomerization Domain

Over the last decade, innate immune system receptors and sensors called inflammasomes have been identified to play key pathological roles in the development and progression of numerous diseases. Among them, the nucleotide-binding oligomerization domain (NOD-), leucine-rich repeat (LRR-) and pyrin domain-containing protein 3 (NLRP3) inflammasome is probably the best characterized. To date, NLRP3 has been extensively studied in the heart, where its effects and actions have been broadly documented in numerous cardiovascular diseases. However, little is still known about NLRP3 implications in muscle disorders affecting non-cardiac muscles. In this review, we summarize and present the current knowledge regarding the function of NLRP3 in diseased skeletal muscle, and discuss the potential therapeutic options targeting the NLRP3 inflammasome in muscle disorders.

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

2018 ◽  
Vol 92 (19) ◽  
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.

scholarly journals SEVELAMER CARBONATE MODULATES THE NLRP3 AND NLRP6 INFLAMMASOME EXPRESSION IN PATIENTS WITH DIABETIC NEPHROPATHY

2021 ◽  
Vol 80 (2) ◽  
pp. 125-132
Author(s):  
Grațiela Grădișteanu Pîrcălăbioru ◽  
Mariana-Carmen Chifiriuc ◽  
Roxana Adriana Stoica
Keyword(s):  
Diabetic Nephropathy ◽  
Nlrp3 Inflammasome ◽  
Treatment Plan ◽  
Innate Immune ◽  
Pentraxin 3 ◽  
Quantitative Real Time Pcr ◽  
Blood Samples ◽  
Sevelamer Carbonate

Interaction of microorganisms with the host innate immune system is a crucial factor that could modify diabetes and its associated complications. Recent reports have elucidated the role of NLRP3 inflammasome in diabetes, but to our knowledge there is no data regarding the role of other inflammasomes in diabetes-induced inflammation. To investigate this, blood samples were collected from type 2 diabetes (T2DM) patients with nephropathy as well as from healthy volunteers. After red blood cell lysis, RNA was isolated from all collected blood samples. The expression of NLRP 6, NLRP3, ASC, PRO-IL1Β, and PRO-IL18 was assessed by quantitative Real Time PCR (qRT-PCR). Patients with diabetic nephropathy showed higher NLRP3 inflammasome expression compared to healthy controls whereas no significant differences were observed in case of NLRP6 inflammasome. In addition, Pentraxin 3 expression was elevated in patients with diabetic nephropathy. A detailed analysis of the patient’s clinical data revealed the fact that subjects receiving sevelamer carbonate in their treatment plan harboured low expression of Pentraxin 3 (PTX3) and NLRP3 associated genes.

scholarly journals Nutrients and Immunometabolism: Role of Macrophage NLRP3

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.

scholarly journals The Diethylcarbamazine Delays and Decreases the NETosis of Polymorphonuclear Cells of Humans with DM Type 2

2020 ◽  
Vol 2020 ◽  
pp. 1-8 ◽  
Author(s):  
Juan C. Segoviano-Ramirez ◽  
Daniel F. Lopez-Altamirano ◽  
Jaime Garcia-Juarez ◽  
Juan E. S. Aguirre-Garza ◽  
Eloy Cárdenas-Estrada ◽  
...  
Keyword(s):  
Metabolic Diseases ◽  
Innate Immune ◽  
High Morbidity ◽  
Polymorphonuclear Cells ◽  
Expected Time ◽  
Human Volunteers ◽  
Plantar Ulcers ◽  
Dm Type 2

Type 2 diabetes mellitus (DM2) is a disease that reports high morbidity and mortality rates worldwide. Between its complications, one of the most important is the development of plantar ulcers. The role of the polymorphonuclear cells (PMNs) is affected by metabolic diseases like DM2. Fifteen years ago, reports about a new mechanism of innate immune response where PMNs generate some kind of webs with their chromatin were published. This mechanism was called NETosis. Also, some researchers have demonstrated that NETosis is responsible for the delay of the ulcer healing both in patients with DM2 and in animal models of DM2. Purified PMNs from healthy and DM2 human volunteers were incubated with diethylcarbamazine (DEC) and then induced to NETosis using phorbol 12-myristate 13-acetate (PMA). In a randomized blind study model, the NETosis was documented by confocal microscopy. On microphotographs, the area of each extracellular neutrophil trap (NET) formed at different times after stimuli with PMA was bounded, and the intensity of fluorescence (IF) from the chromatin dyed with 4′,6-diamidino-2-phenylindole dihydrochloride (DAPI) was quantified. PMNs from healthy volunteers showed the development of NETs at expected times according to the literature. The same phenomenon was seen in cultures of PMNs from metabolically controlled DM2 volunteers. The use of DEC one hour before of the challenge with PMA delayed the NETosis in both groups. The semiquantitative morphometric analysis of the IF from DAPI, as a measure of PMN’s capacity to forming NETs, is consistent with these results. The ANOVA test demonstrated that NETosis was lower and appeared later than expected time, both in PMNs from healthy (p≤0.000001) and from DM2 (p≤0.000477) volunteers. In conclusion, the DEC delays and decreases the NETosis by PMNs from healthy as well as DM2 people.

scholarly journals Pattern Recognition Receptor-Mediated Chronic Inflammation in the Development and Progression of Obesity-Related Metabolic Diseases

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Lili Yu ◽  
Yanhua Li ◽  
Cancan Du ◽  
Weidong Zhao ◽  
Hanxiao Zhang ◽  
...  
Keyword(s):  
Pattern Recognition ◽  
Chronic Inflammation ◽  
Fatty Liver Disease ◽  
Metabolic Diseases ◽  
Important Determinant ◽  
Pattern Recognition Receptor ◽  
Nonalcoholic Fatty Liver ◽  
Recognition Receptor ◽  
Oligomerization Domain

Obesity-induced chronic inflammation is known to promote the development of many metabolic diseases, especially insulin resistance, type 2 diabetes mellitus, nonalcoholic fatty liver disease, and atherosclerosis. Pattern recognition receptor-mediated inflammation is an important determinant for the initiation and progression of these metabolic diseases. Here, we review the major features of the current understanding with respect to obesity-related chronic inflammation in metabolic tissues, focus on Toll-like receptors and nucleotide-binding oligomerization domain-like receptors with an emphasis on how these receptors determine metabolic disease progression, and provide a summary on the development and progress of PRR antagonists for therapeutic intervention.

scholarly journals Regulation of adipogenic differentiation and adipose tissue inflammation by interferon regulatory factor 3

2021 ◽  
Author(s):  
Peng Tang ◽  
Sam Virtue ◽  
Jian Yi Gerald Goie ◽  
Chin Wen Png ◽  
Jing Guo ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Metabolic Diseases ◽  
Adipogenic Differentiation ◽  
Interferon Regulatory Factor ◽  
Therapeutic Interventions ◽  
Regulatory Factor ◽  
Primary Defect ◽  
Interferon Regulatory Factor 3

AbstractDysfunction of adipocytes and adipose tissue is a primary defect in obesity and obesity-associated metabolic diseases. Interferon regulatory factor 3 (IRF3) has been implicated in adipogenesis. However, the role of IRF3 in obesity and obesity-associated disorders remains unclear. Here, we show that IRF3 expression in human adipose tissues is positively associated with insulin sensitivity and negatively associated with type 2 diabetes. In mouse pre-adipocytes, deficiency of IRF3 results in increased expression of PPARγ and PPARγ-mediated adipogenic genes, leading to increased adipogenesis and altered adipocyte functionality. The IRF3 knockout (KO) mice develop obesity, insulin resistance, glucose intolerance, and eventually type 2 diabetes with aging, which is associated with the development of white adipose tissue (WAT) inflammation. Increased macrophage accumulation with M1 phenotype which is due to the loss of IFNβ-mediated IL-10 expression is observed in WAT of the KO mice compared to that in wild-type mice. Bone-marrow reconstitution experiments demonstrate that the nonhematopoietic cells are the primary contributors to the development of obesity and both hematopoietic and nonhematopoietic cells contribute to the development of obesity-related complications in IRF3 KO mice. This study demonstrates that IRF3 regulates the biology of multiple cell types including adipocytes and macrophages to prevent the development of obesity and obesity-related complications and hence, could be a potential target for therapeutic interventions for the prevention and treatment of obesity-associated metabolic disorders.

scholarly journals Interaction between autophagy and the NLRP3 inflammasome

2019 ◽  
Vol 51 (11) ◽  
pp. 1087-1095 ◽  
Author(s):  
Zhenrui Cao ◽  
Yanhao Wang ◽  
Zhimin Long ◽  
Guiqiong He
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Diseases ◽  
Dynamic Balance ◽  
Cell Structure ◽  
Innate Immune ◽  
Interleukin 18 ◽  
Disease Treatment ◽  
Selective Autophagy ◽  
Inflammatory Bowel

Abstract Autophagy, a metabolic pathway that plays an important role in maintaining the dynamic balance of cells, has two types, i.e. non-selective autophagy and selective autophagy. The role of non-selective autophagy is primarily to allow cells to circulate nutrients in an energy-limited environment, while selective autophagy primarily cleans up the organelles inside the cells to maintain the cell structure. The NLRP3 inflammasome is an innate immune response produced by the organism that can promote the secretion of interleukin-1β and interleukin-18 through caspase-1 activation and resist the damage of some pathogens. However, when the NLRP3 inflammasome is overactivated, it can cause various inflammatory diseases, such as inflammatory liver disease and inflammatory bowel disease. Many previous studies have shown that autophagy can inhibit the NLRP3 inflammasome, while in recent years, new studies have found that autophagy can also promote the NLRP3 inflammasome in some cases, and the NLRP3 inflammasome can, in turn, affect autophagy. In this review, the interaction between autophagy and the NLRP3 inflammasome is explored, and then the application of this interaction in disease treatment is discussed.

scholarly journals The Role of the Interplay Between Autophagy and NLRP3 Inflammasome in Metabolic Disorders

2021 ◽  
Vol 9 ◽  
Author(s):  
Shuangyu Lv ◽  
Honggang Wang ◽  
Xiaotian Li
Keyword(s):  
Nlrp3 Inflammasome ◽  
Metabolic Disorders ◽  
Interleukin 1 ◽  
Basic Research ◽  
Interleukin 1 Beta ◽  
Cell Composition ◽  
Pyrin Domain ◽  
Receptor Family ◽  
Oligomerization Domain

Autophagy is an important and conserved cellular pathway in which cells transmit cytoplasmic contents to lysosomes for degradation. It plays an important role in maintaining the balance of cell composition synthesis, decomposition and reuse, and participates in a variety of physiological and pathological processes. The nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome can induce the maturation and secretion of Interleukin-1 beta (IL-1β) and IL-18 by activating caspase-1. It is involved in many diseases. In recent years, the interplay between autophagy and NLRP3 inflammasome has been reported to contribute to many diseases including metabolic disorders related diseases. In this review, we summarized the recent studies on the interplay between autophagy and NLRP3 inflammasome in metabolic disorders to provide ideas for the relevant basic research in the future.

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