scholarly journals Inflammasomes and Fibrosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Wen-Juan Zhang ◽  
Shu-Juan Chen ◽  
Shun-Chang Zhou ◽  
Su-Zhen Wu ◽  
Hui Wang
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Diseases ◽  
Innate Immune ◽  
Receptor Protein ◽  
Activation Process ◽  
Common Pathway ◽  
Classical Activation ◽  
Activation Pathway ◽  
Caspase 1

Fibrosis is the final common pathway of inflammatory diseases in various organs. The inflammasomes play an important role in the progression of fibrosis as innate immune receptors. There are four main members of the inflammasomes, such as NOD-like receptor protein 1 (NLRP1), NOD-like receptor protein 3 (NLRP3), NOD-like receptor C4 (NLRC4), and absent in melanoma 2 (AIM2), among which NLRP3 inflammasome is the most studied. NLRP3 inflammasome is typically composed of NLRP3, ASC and pro-caspase-1. The activation of inflammasome involves both “classical” and “non-classical” pathways and the former pathway is better understood. The “classical” activation pathway of inflammasome is that the backbone protein is activated by endogenous/exogenous stimulation, leading to inflammasome assembly. After the formation of “classic” inflammasome, pro-caspase-1 could self-activate. Caspase-1 cleaves cytokine precursors into mature cytokines, which are secreted extracellularly. At present, the “non-classical” activation pathway of inflammasome has not formed a unified model for activation process. This article reviews the role of NLRP1, NLRP3, NLRC4, AIM2 inflammasome, Caspase-1, IL-1β, IL-18 and IL-33 in the fibrogenesis.

scholarly journals The central role of inflammatory signaling in the pathogenesis of myelodysplastic syndromes

Blood ◽  
2019 ◽  
Vol 133 (10) ◽  
pp. 1039-1048 ◽  
Author(s):  
David A. Sallman ◽  
Alan List
Keyword(s):  
Myelodysplastic Syndromes ◽  
Immune Activation ◽  
Nlrp3 Inflammasome ◽  
Cancer Biology ◽  
Innate Immune ◽  
Cell Swelling ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Innate Immune Activation

Abstract In cancer biology, tumor-promoting inflammation and an inflammatory microenvironment play a vital role in disease pathogenesis. In the past decade, aberrant innate immune activation and proinflammatory signaling within the malignant clone and the bone marrow (BM) microenvironment were identified as key pathogenic drivers of myelodysplastic syndromes (MDS). In particular, S100A9-mediated NOD-like receptor protein 3 (NLRP3) inflammasome activation directs an inflammatory, lytic form of cell death termed pyroptosis that underlies many of the hallmark features of the disease. This circuit and accompanying release of other danger-associated molecular patterns expands BM myeloid-derived suppressor cells, creating a feed-forward process propagating inflammasome activation. Furthermore, somatic gene mutations of varied functional classes license the NLRP3 inflammasome to generate a common phenotype with excess reactive oxygen species generation, Wnt/β-catenin–induced proliferation, cation flux-induced cell swelling, and caspase-1 activation. Recent investigations have shown that activation of the NLRP3 inflammasome complex has more broad-reaching importance, particularly as a possible disease-specific biomarker for MDS, and, mechanistically, as a driver of cardiovascular morbidity/mortality in individuals with age-related, clonal hematopoiesis. Recognition of the mechanistic role of aberrant innate immune activation in MDS provides a new perspective for therapeutic development that could usher in a novel class of disease-modifying agents.

scholarly journals Distinct expression profile and histological distribution of NLRP3 inflammasome components in the tissues of Hainan black goat suggest a site-specific role in the inflammatory response

2017 ◽  
Vol 65 (3) ◽  
pp. 402-416 ◽  
Author(s):  
Kaizhao Zhang ◽  
Pan Tao ◽  
Jianxin Liu ◽  
Qingnan Wang ◽  
Shikun Ge ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Nlrp3 Inflammasome ◽  
Cortical Neurons ◽  
Inflammatory Diseases ◽  
Polyclonal Antibodies ◽  
Receptor Protein ◽  
Mesenteric Lymph Nodes ◽  
Specific Expression ◽  
Caspase 1 ◽  
Black Goat

The NOD-like receptor protein 3 (NLRP3) inflammasome comprised of NLRP3, ASC and caspase-1 plays an important role in the inflammatory and innate immune response. However, little is known about the expression pattern and histological distribution of these genes in goat. Here, we first cloned the fulllength cDNAs of the NLRP3, ASC and caspase-1 genes of Hainan black goat and produced their polyclonal antibodies. Tissue-specific expression and histological distribution of these genes were analysed. Phylogenetic analysis revealed that these three goat genes had high homology with Bos taurus genes and low homology with avian or fish genes. After immunisations with these recombinant Histagged proteins, the titres of antiserum were higher than 1:1024 and purified IgG was obtained. These three genes were expressed in all examined tissues, the mRNA expression level of NLRP3 and caspase-1 was most abundant in the spleen and mesenteric lymph nodes (MLNs), while ASC was primary expressed in the liver, spleen and kidney. The histological distribution of NLRP3, ASC and caspase-1 was detected in myocardial cells, hepatocytes, focal lymphocytes, bronchiolar epithelial cells, renal tubular epithelial cells, cortical neurons and endothelial cells of the germinal centres in the MLNs. These results will be helpful in further investigations into the function of the NLRP3 inflammasome and in elucidating its role in caprine inflammatory diseases.

scholarly journals The Role of the Effects of Autophagy on NLRP3 Inflammasome in Inflammatory Nervous System Diseases

2021 ◽  
Vol 9 ◽  
Author(s):  
Shizhen Zhao ◽  
Xiaotian Li ◽  
jie Wang ◽  
Honggang Wang
Keyword(s):  
Nervous System ◽  
Nlrp3 Inflammasome ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cerebral Hypoperfusion ◽  
Receptor Protein ◽  
Future Research ◽  
Nervous System Diseases ◽  
Caspase 1

Autophagy is a stable self-sustaining process in eukaryotic cells. In this process, pathogens, abnormal proteins, and organelles are encapsulated by a bilayer membrane to form autophagosomes, which are then transferred to lysosomes for degradation. Autophagy is involved in many physiological and pathological processes. Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome, containing NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and pro-caspase-1, can activate caspase-1 to induce pyroptosis and lead to the maturation and secretion of interleukin-1 β (IL-1 β) and IL-18. NLRP3 inflammasome is related to many diseases. In recent years, autophagy has been reported to play a vital role by regulating the NLRP3 inflammasome in inflammatory nervous system diseases. However, the related mechanisms are not completely clarified. In this review, we sum up recent research about the role of the effects of autophagy on NLRP3 inflammasome in Alzheimer’s disease, chronic cerebral hypoperfusion, Parkinson’s disease, depression, cerebral ischemia/reperfusion injury, early brain injury after subarachnoid hemorrhage, and experimental autoimmune encephalomyelitis and analyzed the related mechanism to provide theoretical reference for the future research of inflammatory neurological diseases.

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 Role of ASM/Cer/TXNIP signaling module in the NLRP3 inflammasome activation

2020 ◽  
Author(s):  
Jianjun Jiang ◽  
Jin Yang ◽  
Yining Shi ◽  
Jiyu Cao ◽  
Youjin Lu ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Underlying Mechanism ◽  
Acid Sphingomyelinase ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Mrna Levels ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation

Abstract Background: The NOD-Like Receptor Protein 3 (NLRP3) inflammasome is a crucial component of an array of inflammatory conditions. It functions by boosting the secretion of pro-inflammatory cytokines: interleukin-1β (IL-1β) and interleukin-18 (IL-18). Previous studies have established the vital role of the acid sphingomyelinase (ASM)/ceramide (Cer) pathway in the functional outcome of cells, with a particular emphasis on the inflammatory processes. This study aimed to explore the effects and associated underlying mechanism of Cer-induced NLRP3 inflammasome activation.Methods: Lipopolysaccharide (LPS)/adenosine triphosphate (ATP)-induced NLRP3 inflammasome activation in J774A.1 cells was used as an in vitro inflammatory model. Western blotting and Real-time PCR (RT-PCR) were used to detect the protein and mRNA levels, respectively. IL-1β and IL-18 levels were evaluated using ELISA kits. ASM assay kit and immunofluorescence were used to detect ASM activity and Cer content.Results: Imipramine, a well-known inhibitor of ASM, significantly inhibited ASM activity and inhibited Cer accumulation, which indicated ASM activation. Besides, it also suppressed the LPS/ATP-induced expression of proteins and mRNA: thioredoxin interacting protein (TXNIP), NLRP3, caspase-1, IL-1β and IL-18. Interestingly verapamil, a TXNIP inhibitor, suppressed LPS/ATP-induced TXNIP/NLRP3 inflammasome activation; however, it did not affect LPS/ATP-induced ASM activation and ceramide production. Further analysis showed that the exogenous C2-Cer treated J774A.1 cells induced the overexpression of TXNIP, NLRP3, caspase-1, IL-1β and IL-18. Besides, TXNIP siRNA or verapamil inhibited C2-Cer-induced TXNIP overexpression and NLRP3 inflammasome activation.Conclusion: This study demonstrated the involvement of the ASM/Cer/TXNIP signaling pathway in NLRP3 inflammasome activation.

scholarly journals Nuclear Receptors in the Control of the NLRP3 Inflammasome Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Hélène Duez ◽  
Benoit Pourcet
Keyword(s):  
Immune System ◽  
Nuclear Receptors ◽  
Nlrp3 Inflammasome ◽  
Innate Immune System ◽  
Inflammatory Diseases ◽  
Ischemia Reperfusion ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Brain Diseases ◽  
Caspase 1

The innate immune system is the first line of defense specialized in the clearing of invaders whether foreign elements like microbes or self-elements that accumulate abnormally including cellular debris. Inflammasomes are master regulators of the innate immune system, especially in macrophages, and are key sensors involved in maintaining cellular health in response to cytolytic pathogens or stress signals. Inflammasomes are cytoplasmic complexes typically composed of a sensor molecule such as NOD-Like Receptors (NLRs), an adaptor protein including ASC and an effector protein such as caspase 1. Upon stimulation, inflammasome complex components associate to promote the cleavage of the pro-caspase 1 into active caspase-1 and the subsequent activation of pro-inflammatory cytokines including IL-18 and IL-1β. Deficiency or overactivation of such important sensors leads to critical diseases including Alzheimer diseases, chronic inflammatory diseases, cancers, acute liver diseases, and cardiometabolic diseases. Inflammasomes are tightly controlled by a two-step activation regulatory process consisting in a priming step, which activates the transcription of inflammasome components, and an activation step which leads to the inflammasome complex formation and the subsequent cleavage of pro-IL1 cytokines. Apart from the NF-κB pathway, nuclear receptors have recently been proposed as additional regulators of this pathway. This review will discuss the role of nuclear receptors in the control of the NLRP3 inflammasome and the putative beneficial effect of new modulators of inflammasomes in the treatment of inflammatory diseases including colitis, fulminant hepatitis, cardiac ischemia–reperfusion and brain diseases.

scholarly journals NLRP3 and Infections: β-Amyloid in Inflammasome beyond Neurodegeneration

2021 ◽  
Vol 22 (13) ◽  
pp. 6984
Author(s):  
Giulia Sita ◽  
Agnese Graziosi ◽  
Patrizia Hrelia ◽  
Fabiana Morroni
Keyword(s):  
Systemic Inflammation ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Diseases ◽  
Innate Immune ◽  
Inflammasome Activation ◽  
Low Grade ◽  
Pathological Feature ◽  
Research Focus ◽  
Β Amyloid

Amyloid beta (Aβ)-induced abnormal neuroinflammation is recognized as a major pathological feature of Alzheimer’s disease (AD), which results in memory impairment. Research exploring low-grade systemic inflammation and its impact on the development and progression of neurodegenerative disease has increased. A particular research focus has been whether systemic inflammation arises only as a secondary effect of disease, or it is also a cause of pathology. The inflammasomes, and more specifically the NLRP3 inflammasome, are crucial components of the innate immune system and are usually activated in response to infection or tissue damage. Although inflammasome activation plays critical roles against various pathogens in host defense, overactivation of inflammasome contributes to the pathogenesis of inflammatory diseases, including acute central nervous system (CNS) injuries and chronic neurodegenerative diseases, such as AD. This review summarizes the current literature on the role of the NLRP3 inflammasome in the pathogenesis of AD, and its involvement in infections, particularly SARS-CoV-2. NLRP3 might represent the crossroad between the hypothesized neurodegeneration and the primary COVID-19 infection.

NLRP3 regulates macrophage M2 polarization through up-regulation of IL-4 in asthma

2018 ◽  
Vol 475 (12) ◽  
pp. 1995-2008 ◽  
Author(s):  
Ying Liu ◽  
Xin Gao ◽  
Yi Miao ◽  
Yuanyuan Wang ◽  
Huan Wang ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Diseases ◽  
Allergic Inflammation ◽  
Lavage Fluid ◽  
Interferon Γ ◽  
Receptor Protein ◽  
Loss Of Function ◽  
Caspase 1 ◽  
M2 Polarization ◽  
Factor Α

Activation of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome received substantial attention recently in inflammatory diseases. Macrophages contribute to allergic inflammation in asthma. The present study was aimed to investigate the effect of NLRP3 inflammasome on the polarization of macrophages. We utilized human primary monocytes and monocyte-derived macrophages to study the expression of NLRP3 inflammasome components (NLRP3, apoptosis-associated specklike protein, and caspase-1) and its downstream cytokine interleukin-1β (IL-1β). By gain- or loss-of-function assays, we next explored the effects of NLRP3 inflammasome on M1/M2 polarization and secretion of IL-4, interferon-γ, tumor necrosis factor-α, and IL-1β. The results showed increased numbers of M2 cells in asthma. And NLRP3 inflammasome was activated and involved in the inflammation of asthma. Furthermore, silence of NLRP3 down-regulated IL-4 secretion and up-regulated M1/M2. In contrast, overexpression of NLRP3 increased IL-4 and decreased M1/M2. As expected, IL-4 was involved in NLRP3-mediated down-regulation of Ml/M2 ratio. Moreover, NLRP3 interacted with IRF4 and was required for optimal IRF4-dependent IL-4 transcription. Subsequently, deficiency of NLRP3 in ovalbumin-induced allergic asthmatic mice impaired lung inflammation and up-regulated M1/M2, and diminished IL-4 in bronchoalveolar lavage fluid. Collectively, we demonstrated here that activation of NLRP3 was engaged in the promotion of asthma. NLRP3, but not the inflammasome adaptor ASC or caspase-1, promoted the polarization of M2 macrophages through up-regulating the expression of IL-4, thereby contributing to its regulation of asthma.

scholarly journals Structural Moieties Required for Cinnamaldehyde-Related Compounds to Inhibit Canonical IL-1β Secretion

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3241 ◽  
Author(s):  
Su-Chen Ho ◽  
Yi-Huang Chang ◽  
Ku-Shang Chang
Keyword(s):  
Nlrp3 Inflammasome ◽  
Functional Group ◽  
Inflammatory Diseases ◽  
Receptor Protein ◽  
Side Chain ◽  
Activated Macrophages ◽  
Inhibitory Effects ◽  
Chronic Inflammatory Diseases ◽  
Caspase 1 ◽  
Related Compounds

Suppressing canonical NOD-like receptor protein 3 (NLRP3) inflammasome-mediated interleukin (IL)-1β secretion is a reliable strategy for the development of nutraceutical to prevent chronic inflammatory diseases. This study aimed to find out the functional group responsible for the inhibitory effects of cinnamaldehyde-related compounds on the canonical IL-1β secretion. To address this, the suppressing capacities of six cinnamaldehyde-related compounds were evaluated and compared by using the lipopolysaccharide (LPS)-primed and adenosine 5′-triphosphate (ATP)-activated macrophages. At concentrations of 25~100 μM, cinnamaldehyde and 2-methoxy cinnamaldehyde dose-dependently inhibited IL-1β secretion. In contrast, cinnamic acid, cinnamyl acetate, cinnamyl alcohol and α-methyl cinnamaldehyde did not exert any inhibition. Furthermore, cinnamaldehyde and 2-methoxy cinnamaldehyde diminished expressions of NLRP3 and pro-IL-1β. Meanwhile, cinnamaldehyde and 2-methoxy cinnamaldehyde prevented the ATP-induced reduction of cytosolic pro-caspase-1 and increase of secreted caspase-1. In conclusion, for cinnamaldehyde-related compounds to suppress NLRP3 inflammasome-mediated IL-1β secretion, the propenal group of the side chain was essential, while the substituted group of the aromatic ring played a modifying role. Cinnamaldehyde and 2-methoxy cinnamaldehyde exerted dual abilities to inhibit canonical IL-1β secretion at both stages of priming and activation. Therefore, there might be potential to serve as complementary supplements for the prevention of chronic inflammatory diseases.

scholarly journals Role of ASM/Cer/TXNIP Signaling Module in the NLRP3 Inflammasome Activation

2020 ◽  
Author(s):  
Jianjun Jiang ◽  
Jin Yang ◽  
Yining Shi ◽  
Jiyu Cao ◽  
Youjin Lu ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Drug Targets ◽  
Inflammatory Diseases ◽  
Acid Sphingomyelinase ◽  
Inflammasome Activation ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation ◽  
Ceramide Production

Abstract Background: The NLRP3 inflammasome serves as a crucial component in an array of inflammatory conditions by boosting the secretion of pro-inflammatory cytokines: IL-1β and IL-18. Hence, a thorough investigation of the underlying mechanism of NLRP3 activation could ascertain the requisite directionality to the ongoing studies, along with the identification of the novel drug targets for the management of inflammatory diseases. Previous studies have established the vital role of the Acid sphingomyelinase (ASM)/Ceramide (Cer) pathway in the functional outcome of cells, with a particular emphasis on the inflammatory processes. ASM mediates the ceramide production by sphingomyelin hydrolysis. Furthermore, the participation of the ASM/Cer in NLRP3 activation remains ambiguous. Methods: We employed lipopoysaccharide (LPS)/Adenosine Triphosphate (ATP)-induced activation of NLRP3 inflammasome in J774A.1 cells as an in vitro inflammatory model. Results: We observed that imipramine, a well-known inhibitor of ASM, significantly inhibited ASM activity & increased ceramide accumulation, which indicates ASM activation. Besides, it also suppressed the LPS/ATP-induced expression of proteins and mRNA: Thioredoxin interacting protein (TXNIP), NLRP3, Caspase-1, IL-1β and IL-18. Interestingly verapamil, a TXNIP inhibitor, suppressed LPS/ATP-induced TXNIP/NLRP3 inflammasome activation; however, it did not affect LPS/ATP-induced ASM activity and ceramide production. Further examination showed that the exogenous C2-ceramide-treated J774A.1 cells induce the overexpression of TXNIP, NLRP3, Caspase-1, IL-1β, and IL-18. Furthermore, verapamil inhibited C2-Ceramide mediated TXNIP overexpression and NLRP3 inflammasome activation. These findings infer that TXNIP overexpression leads to Cer mediated NLRP3 inflammasome activation. Conclusion: Our study validated the crucial role of the ASM/Cer/TXNIP signaling pathway in NLRP3 inflammasome activation.

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