scholarly journals Gut–Liver Axis and Inflammasome Activation in Cholangiocyte Pathophysiology

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 736 ◽  
Author(s):  
Luca Maroni ◽  
Elisabetta Ninfole ◽  
Claudio Pinto ◽  
Antonio Benedetti ◽  
Marco Marzioni
Keyword(s):  
Nlrp3 Inflammasome ◽  
Current Knowledge ◽  
Strong Association ◽  
Inflammasome Activation ◽  
Bacterial Composition ◽  
Nlrp3 Inflammasome Activation ◽  
Inflammatory Processes ◽  
Inflammatory Bowel ◽  
Bacterial Products

The Nlrp3 inflammasome is a multiprotein complex activated by a number of bacterial products or danger signals and is involved in the regulation of inflammatory processes through caspase-1 activation. The Nlrp3 is expressed in immune cells but also in hepatocytes and cholangiocytes, where it appears to be involved in regulation of biliary damage, epithelial barrier integrity and development of fibrosis. Activation of the pathways of innate immunity is crucial in the pathophysiology of hepatobiliary diseases, given the strong link between the gut and the liver. The liver secretes bile acids, which influence the bacterial composition of the gut microbiota and, in turn, are heavily modified by microbial metabolism. Alterations of this balance, as for the development of dysbiosis, may deeply influence the composition of the bacterial products that reach the liver and are able to activate a number of intracellular pathways. This alteration may be particularly important in the pathogenesis of cholangiopathies and, in particular, of primary sclerosing cholangitis, given its strong association with inflammatory bowel disease. In the present review, we summarize current knowledge on the gut–liver axis in cholangiopathies and discuss the role of Nlrp3 inflammasome activation in cholestatic conditions.

scholarly journals Role of NLRP3 Inflammasomes in Neuroinflammation Diseases

2020 ◽  
pp. 1-5
Author(s):  
Sen Lin ◽  
Xifan Mei
Keyword(s):  
Nlrp3 Inflammasome ◽  
Current Knowledge ◽  
Inflammasome Activation ◽  
Protein Signaling ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation ◽  
Inflammatory Immune Response ◽  
Nlrp3 Inflammasomes ◽  
Pro Inflammatory Cytokines

<b><i>Background:</i></b> Inflammasomes are large intracellular multi-protein signaling complexes that are formed in the cytosolic compartment as an inflammatory immune response to endogenous danger signals. The formation of the inflammasome enables activation of an inflammatory protease caspase-1 and pyroptosis initiation with the subsequent cleaving of the pro-inflammatory cytokines interleukin (IL)-1β and proIL-18 to produce active forms. The inflammasome complex consists of a nod-like receptor, the adapter apoptosis-associated speck-like protein, and caspase-1. Dysregulation of NLRP3 inflammasome activation is involved in neuroinflammation disease pathogenesis, although its role in SCI development and progression remains controversial due to the inconsistent findings described. <b><i>Summary:</i></b> In this review, we summarize the current knowledge on the contribution of the NLRP3 inflammasome on potential neuroinflammation diseases therapy.

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

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Elisa Benetti ◽  
Fausto Chiazza ◽  
Nimesh S. A. Patel ◽  
Massimo Collino
Keyword(s):  
Chronic Inflammation ◽  
Nlrp3 Inflammasome ◽  
Metabolic Disorders ◽  
Inflammasome Activation ◽  
Nucleotide Binding Domain ◽  
Metabolic Inflammation ◽  
Nlrp3 Inflammasome Activation ◽  
Leucine Rich Repeat Protein

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.

scholarly journals Galectin-3 in Inflammasome Activation and Primary Biliary Cholangitis Development

2020 ◽  
Vol 21 (14) ◽  
pp. 5097
Author(s):  
Aleksandar Arsenijevic ◽  
Bojana Stojanovic ◽  
Jelena Milovanovic ◽  
Dragana Arsenijevic ◽  
Nebojsa Arsenijevic ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Animal Studies ◽  
Current Knowledge ◽  
Specific Binding ◽  
Primary Biliary Cholangitis ◽  
Inflammasome Activation ◽  
Multimeric Complex ◽  
Galectin 3 ◽  
Binding Lectin

Primary biliary cholangitis (PBC) is a chronic inflammatory autoimmune liver disease characterized by inflammation and damage of small bile ducts. The NLRP3 inflammasome is a multimeric complex of proteins that after activation with various stimuli initiates an inflammatory process. Increasing data obtained from animal studies implicate the role of NLRP3 inflammasome in the pathogenesis of various diseases. Galectin-3 is a β-galactoside-binding lectin that plays important roles in various biological processes including cell proliferation, differentiation, transformation and apoptosis, pre-mRNA splicing, inflammation, fibrosis and host defense. The multilineage immune response at various stages of PBC development includes the involvement of Gal-3 in the pathogenesis of this disease. The role of Galectin-3 in the specific binding to NLRP3, and inflammasome activation in models of primary biliary cholangitis has been recently described. This review provides a brief pathogenesis of PBC and discusses the current knowledge about the role of Gal-3 in NLRP3 activation and PBC development.

scholarly journals The role of NLRP3 inflammasome activation in radiation damage

2019 ◽  
Vol 118 ◽  
pp. 109217 ◽  
Author(s):  
Jinlong Wei ◽  
Heru Wang ◽  
Huanhuan Wang ◽  
Bin Wang ◽  
Lingbin Meng ◽  
...  
Keyword(s):  
Radiation Damage ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation

scholarly journals Distinct Molecular Mechanisms Underlying Potassium Efflux for NLRP3 Inflammasome Activation

2020 ◽  
Vol 11 ◽  
Author(s):  
Ziwei Xu ◽  
Zi-mo Chen ◽  
Xiaoyan Wu ◽  
Linjie Zhang ◽  
Ying Cao ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Inflammasome Activation ◽  
Potassium Efflux ◽  
Pannexin 1 ◽  
Nlrp3 Inflammasome Activation ◽  
K2p Channels ◽  
Pore Forming Proteins ◽  
Molecular Patterns

The NLRP3 inflammasome is a core component of innate immunity, and dysregulation of NLRP3 inflammasome involves developing autoimmune, metabolic, and neurodegenerative diseases. Potassium efflux has been reported to be essential for NLRP3 inflammasome activation by structurally diverse pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Thus, the molecular mechanisms underlying potassium efflux to activate NLRP3 inflammasome are under extensive investigation. Here, we review current knowledge about the distinction channels or pore-forming proteins underlying potassium efflux for NLRP3 inflammasome activation with canonical/non-canonical signaling or following caspase-8 induced pyroptosis. Ion channels and pore-forming proteins, including P2X7 receptor, Gasdermin D, pannexin-1, and K2P channels involved present viable therapeutic targets for NLRP3 inflammasome related diseases.

scholarly journals ROS-Mediated NLRP3 Inflammasome Activation in Brain, Heart, Kidney, and Testis Ischemia/Reperfusion Injury

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Letteria Minutoli ◽  
Domenico Puzzolo ◽  
Mariagrazia Rinaldi ◽  
Natasha Irrera ◽  
Herbert Marini ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Current Knowledge ◽  
Ischemia Reperfusion ◽  
Ion Homeostasis ◽  
Inflammasome Activation ◽  
Mortality And Morbidity ◽  
Arterial Blood ◽  
Nlrp3 Inflammasome Activation

Ischemia and reperfusion (I/R) causes a reduction in arterial blood supply to tissues, followed by the restoration of perfusion and consequent reoxygenation. The reestablishment of blood flow triggers further damage to the ischemic tissue through reactive oxygen species (ROS) accumulation, interference with cellular ion homeostasis, and inflammatory responses to cell death. In normal conditions, ROS mediate important beneficial responses. When their production is prolonged or elevated, harmful events are observed with peculiar cellular changes. In particular, during I/R, ROS stimulate tissue inflammation and induce NLRP3 inflammasome activation. The mechanisms underlying the activation of NLRP3 are several and not completely elucidated. It was recently shown that NLRP3 might sense directly the presence of ROS produced by normal or malfunctioning mitochondria or indirectly by other activators of NLRP3. Aim of the present review is to describe the current knowledge on the role of NLRP3 in some organs (brain, heart, kidney, and testis) after I/R injury, with particular regard to the role played by ROS in its activation. Furthermore, as no specific therapy for the prevention or treatment of the high mortality and morbidity associated with I/R is available, the state of the art of the development of novel therapeutic approaches is illustrated.

scholarly journals NADPH Oxidase 2 Regulates NLRP3 Inflammasome Activation in the Brain after Traumatic Brain Injury

2017 ◽  
Vol 2017 ◽  
pp. 1-18 ◽  
Author(s):  
Merry W. Ma ◽  
Jing Wang ◽  
Krishnan M. Dhandapani ◽  
Darrell W. Brann
Keyword(s):  
Oxidative Stress ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Nadph Oxidase ◽  
Nlrp3 Inflammasome ◽  
Healing Process ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Nadph Oxidase 2

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. After the initial primary mechanical injury, a complex secondary injury cascade involving oxidative stress and neuroinflammation follows, which may exacerbate the injury and complicate the healing process. NADPH oxidase 2 (NOX2) is a major contributor to oxidative stress in TBI pathology, and inhibition of NOX2 is neuroprotective. The NLRP3 inflammasome can become activated in response to oxidative stress, but little is known about the role of NOX2 in regulating NLRP3 inflammasome activation following TBI. In this study, we utilized NOX2 knockout mice to study the role of NOX2 in mediating NLRP3 inflammasome expression and activation following a controlled cortical impact. Expression of NLRP3 inflammasome components NLRP3 and apoptosis-associated speck-like protein containing a CARD (ASC), as well as its downstream products cleaved caspase-1 and interleukin-1β (IL-1β), was robustly increased in the injured cerebral cortex following TBI. Deletion of NOX2 attenuated the expression, assembly, and activity of the NLRP3 inflammasome via a mechanism that was associated with TXNIP, a sensor of oxidative stress. The results support the notion that NOX2-dependent inflammasome activation contributes to TBI pathology.

The role of HIF-1α in regulating NLRP3 inflammasome activation in bladder cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17028-e17028 ◽  
Author(s):  
Yuan-Ru Chen ◽  
Hsin-Chih Yeh ◽  
Fang-Yen Chiu ◽  
Hsin-En Wu ◽  
Huei-Chen Fang ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Urothelial Carcinoma ◽  
Cancer Cells ◽  
Nlrp3 Inflammasome ◽  
Migration And Invasion ◽  
Inflammasome Activation ◽  
T24 Cells ◽  
Nlrp3 Inflammasome Activation ◽  
Bladder Cancer Cells

e17028 Background: Bladder cancer is one of the most common malignancies of urinary system with the forth incidence rate and the eighth leading mortality rate in male genitourinary tumors. Hypoxia environment activates the hypoxia‐signalling pathway, principally via hypoxia‐inducible transcription factors (HIF) to activate numerous target genes which mediate embryonic vascularization, metabolism, tumor angiogenesis and the other processes to supply tissues with blood and oxygen. Inflammasomes are multiprotein signal responsible for the maturation of proinflammatory cytokines IL-1β and IL-18 as well as trigger the inflammatory cell pyroptosis. Recent study showed that HIF-1α promotes NLRP3 inflammasome activation in bleomycin-induced acute lung injury. However, the role of HIF1α in regulating the progression of bladder cancer has not been examined so far. The present study aimed to investigate the effect of HIF-1α on NLRP3 inflammasome activation in urothelial carcinoma. Methods: In this research, urothelial carcinoma cell lines were treated with NLRP3 inflammasome inducers, LPS/ATP, to induce NLRP3 inflammasome activation. Results: Our preliminary results showed that both T24 and 5637 bladder cancer cells can be induced NLRP3 inflammasome activation and IL-1β secretion. In addition, hypoxia also induces the secretion of IL-1β in T24 cells. We further investigated the effect of NLRP3 inflammasome activation in modulating EMT-related protein levels, migration and invasion in bladder cancer T24 cells. Our results demonstrated that NLRP3 inflammasome activation promotes tumor growth and metastasis in bladder cancer cells. Furthermore, knockdown of HIF1α reduces both inflammatory response and migratory activity in bladder cancer. Conclusions: Collectively, these results suggest that targeting NLRP3 inflammasome might offer potential to treat hypoxic malignant tumor in bladder carcinoma.

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