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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (15 February 2023) | Viewed by 15372

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Prof. Dr. Kuo-Feng Hua

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Department of Biotechnology and Animal Science, National Ilan University, Yilan 26047, Taiwan
Interests: inflammation; NLRP3 inflammasome; anti-inflammatory; anti-cancer drug development
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Inflammasomes are cytosolic caspase-1-containing protein complexes that recognize and respond to pathogen infection and diverse sterile host-derived or environmental danger signals to promote inflammatory disease development. Activation of inflammasomes leads to caspase-1-dependent maturation and release of the proinflammatory cytokines IL-1β and IL-18 and promotes Gasdermin D-dependent pyroptotic cell death. Dysregulation of inflammasomes is associated with a number of inflammatory conditions, such as COVID-19, metabolic disorders, diabetes, cardiovascular diseases, neurodegenerative diseases, inflammatory bowel disease, kidney injury, and infectious diseases. As inflammasomes respond to a broad range of medically relevant stimuli, inflammasomes have become a highly desirable drug target to treat a wide range of human diseases. Small molecule inhibitors targeting inflammasomes offer a new therapeutic strategy in new drug development. This Special Issue, “New insights into Inflammasomes”, welcomes original research and review articles in the field, with a focus on, but not limited to, the molecular and mechanistic basis for inflammasome activation, inflammasome-associated pathogenesis, inflammasome inhibitor development, and inflammasome-specific therapeutics.

Prof. Dr. Kuo-Feng Hua
Guest Editor

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Keywords

inflammasome
inflammatory disease
caspase-1
cytokines
pyroptosis
NLRP3
inflammasome inhibitor
sterile inflammation

Published Papers (6 papers)

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Research

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13 pages, 1479 KiB

Open AccessCommunication

Antiretrovirals Promote Insulin Resistance in HepG2 Liver Cells through miRNA Regulation and Transcriptional Activation of the NLRP3 Inflammasome

by Jivanka Mohan, Terisha Ghazi, Makabongwe S. Mazibuko and Anil A. Chuturgoon

Int. J. Mol. Sci. 2023, 24(7), 6267; https://doi.org/10.3390/ijms24076267 - 27 Mar 2023

Viewed by 1422

Abstract

Metabolic syndrome (MetS) is a non-communicable disease characterized by a cluster of metabolic irregularities. Alarmingly, the prevalence of MetS in people living with Human Immunodeficiency Virus (HIV) and antiretroviral (ARV) usage is increasing rapidly. Insulin resistance is a common characteristic of MetS that leads to the development of Type 2 diabetes mellitus (T2DM). The progression of insulin resistance is strongly linked to inflammasome activation. This study aimed to draw links between the combinational use of Tenofovir disoproxil fumarate (TDF), Lamivudine (3TC), and Dolutegravir (DTG), and inflammasome activation and subsequent promotion of insulin resistance following a 120 h treatment period in HepG2 liver in vitro cell model. Furthermore, we assess microRNA (miR-128a) expression as a negative regulator of the IRS1/AKT signaling pathway. The relative expression of phosphorylated IRS1 was determined by Western blot. Transcript levels of NLRP3, IL-1β, JNK, IRS1, AKT, PI3K, and miR-128a were assessed using quantitative PCR (qPCR). Caspase-1 activity was measured using luminometry. Following exposure to ARVs for 120 h, NLRP3 mRNA expression (p = 0.0500) and caspase-1 activity (p < 0.0001) significantly increased. This was followed by a significant elevation in IL-1β in mRNA expression (p = 0.0015). Additionally, JNK expression (p = 0.0093) was upregulated with coinciding increases in p-IRS1 protein expression (p < 0.0001) and decreased IRS1 mRNA expression (p = 0.0004). Consequently, decreased AKT (p = 0.0005) and PI3K expressions (p = 0.0007) were observed. Interestingly miR-128a expression was significantly upregulated. The results indicate that combinational use of ARVs upregulates inflammasome activation and promotes insulin resistance through dysregulation of the IRS1/PI3K/AKT insulin signaling pathway. Full article

(This article belongs to the Special Issue New Insights into Inflammasomes)

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13 pages, 2557 KiB

Open AccessArticle

The Organogermanium Compound 3-(Trihydroxygermyl) Propanoic Acid (THGP) Suppresses Inflammasome Activation Via Complexation with ATP

by Junya Azumi, Yasuhiro Shimada, Tomoya Takeda, Hisashi Aso and Takashi Nakamura

Int. J. Mol. Sci. 2022, 23(21), 13364; https://doi.org/10.3390/ijms232113364 - 01 Nov 2022

Cited by 7 | Viewed by 2049

Abstract

Inflammasome activity is a key indicator of inflammation. The inflammasome is activated by pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), which activate the p38-NF-κB pathway and promote IL-1β transcription (signaling step 1). Next, extracellular adenosine triphosphate (ATP) activates the inflammasome (a protein complex consisting of a signal recognition protein, an adapter protein, and Caspase-1) and secretion of inflammatory cytokines such as IL-1β (signaling step 2). Inflammasome activation causes excessive inflammation, leading to inflammasome-active diseases such as atherosclerosis and type 2 diabetes. A hydrolysate of the organogermanium compound Ge-132, 3-(Trihydroxygermyl) propanoic acid (THGP) can form a complex with a cis-diol structure. We investigated the inhibitory effect of THGP on inflammasome activity in human THP-1 monocytes. THGP inhibited IL-1β secretion and caspase-1 activation (signaling step 2) in an ATP-dependent manner. On the other hand, THGP did not suppress IL-1β secretion induced by only lipopolysaccharide (LPS) stimulation. In addition, as IL-6 is an ATP-independent inflammatory cytokine, THGP did not decrease its secretion. THGP also suppressed pyroptosis, which is a caspase-1 activity-dependent form of cell death. Therefore, THGP is expected to become a new therapeutic or prophylactic agent for inflammasome-associated diseases. Full article

(This article belongs to the Special Issue New Insights into Inflammasomes)

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15 pages, 7132 KiB

Open AccessArticle

Microbe-Derived Antioxidants Reduce Lipopolysaccharide-Induced Inflammatory Responses by Activating the Nrf2 Pathway to Inhibit the ROS/NLRP3/IL-1β Signaling Pathway

by Cheng Shen, Zhen Luo, Sheng Ma, Chengbing Yu, Qingying Gao, Meijuan Zhang, Hongcai Zhang, Jing Zhang, Weina Xu, Jianbo Yao and Jianxiong Xu

Int. J. Mol. Sci. 2022, 23(20), 12477; https://doi.org/10.3390/ijms232012477 - 18 Oct 2022

Cited by 7 | Viewed by 1631

Abstract

Inflammation plays an important role in the innate immune response, yet overproduction of inflammation can lead to a variety of chronic diseases associated with the innate immune system; therefore, modulation of the excessive inflammatory response has been considered a major strategy in the treatment of inflammatory diseases. Activation of the ROS/NLRP3/IL-1β signaling axis has been suggested to be a key initiating phase of inflammation. Our previous study found that microbe-derived antioxidants (MA) are shown to have excellent antioxidant and anti-inflammatory properties; however, the mechanism of action of MA remains unclear. The current study aims to investigate whether MA could protect cells from LPS-induced oxidative stress and inflammatory responses by modulating the Nrf2-ROS-NLRP3-IL-1β signaling pathway. In this study, we find that MA treatment significantly alleviates LPS-induced oxidative stress and inflammatory responses in RAW264.7 cells. MA significantly reduce the accumulation of ROS in RAW264.7 cells, down-regulate the levels of pro-inflammatory factors (TNF-α and IL-6), inhibit NLRP3, ASC, caspase-1 mRNA, and protein levels, and reduce the mRNA, protein levels, and content of inflammatory factors (IL-1β and IL-18). The protective effect of MA is significantly reduced after the siRNA knockdown of the NLRP3 gene, presumably related to the ability of MA to inhibit the ROS-NLRP3-IL-1β signaling pathway. MA is able to reduce the accumulation of ROS and alleviate oxidative stress by increasing the content of antioxidant enzymes, such as SOD, GSH-Px, and CAT. The protective effect of MA may be due to its ability of MA to induce Nrf2 to enter the nucleus and initiate the expression of antioxidant enzymes. The antioxidant properties of MA are further enhanced in the presence of the Nrf2 activator SFN. After the siRNA knockdown of the Nrf2 gene, the antioxidant and anti-inflammatory properties of MA are significantly affected. These findings suggest that MA may inhibit the LPS-stimulated ROS/NLRP3/IL-1β signaling axis by activating Nrf2-antioxidant signaling in RAW264.7 cells. As a result of this study, MA has been found to alleviate inflammatory responses and holds promise as a therapeutic agent for inflammation-related diseases. Full article

(This article belongs to the Special Issue New Insights into Inflammasomes)

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16 pages, 3948 KiB

Open AccessArticle

An Experimental Study Reveals the Protective Effect of Autophagy against Realgar-Induced Liver Injury via Suppressing ROS-Mediated NLRP3 Inflammasome Pathway

by Jing Yang, Jian Li, Haoqi Guo, Yuwei Zhang, Ziwei Guo, Yu Liu and Taoguang Huo

Int. J. Mol. Sci. 2022, 23(10), 5697; https://doi.org/10.3390/ijms23105697 - 19 May 2022

Cited by 7 | Viewed by 1999

Abstract

Realgar, a poisonous traditional Chinese medicine, has been shown to cause liver injury when used for long periods or overdoses. However, the underlying molecular mechanisms and therapeutic targets have not been fully elucidated. The aim of this study is to explore the role of autophagy in sub-chronic realgar exposure-induced liver injury. Here, the liver injury model was established by continuously administrating mice with 1.35 g/kg realgar for 8 weeks. 3-methyladenine (3-MA) and rapamycin (RAPA) were used to regulate autophagy. The results showed that realgar induced abnormal changes in liver function, pathological morphology, expression of inflammatory cytokines, and upregulated NLRP3 inflammasome pathway in mouse livers. RAPA treatment (an inducer of autophagy) significantly improved realgar-induced liver injury and NLRP3 inflammasome activation, while 3-MA (an inhibitor of autophagy) aggravated the realgar-induced liver injury and NLRP3 inflammasome activation. Furthermore, we found that realgar-induced NLRP3 inflammasome activation in mouse livers is mediated by ROS. RAPA eliminates excessive ROS, inhibits NF-κB nuclear translocation and down-regulates the TXNIP/NLRP3 axis, consequently suppressing ROS-mediated NLRP3 inflammasome activation, which may be the underlying mechanism of the protective effect of autophagy on realgar-induced liver injury. In conclusion, the results of this study suggest that autophagy alleviates realgar-induced liver injury by inhibiting ROS-mediated NLRP3 inflammasome activation. Autophagy may represent a therapeutic target in modulating realgar-induced liver injury. Full article

(This article belongs to the Special Issue New Insights into Inflammasomes)

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Review

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14 pages, 1043 KiB

Open AccessReview

NLRP3 Inflammasome: From Pathophysiology to Therapeutic Target in Major Depressive Disorder

by Bruna R. Kouba, Joana Gil-Mohapel and Ana Lúcia S. Rodrigues

Int. J. Mol. Sci. 2023, 24(1), 133; https://doi.org/10.3390/ijms24010133 - 21 Dec 2022

Cited by 14 | Viewed by 2877

Abstract

Major depressive disorder (MDD) is a highly prevalent psychiatric disorder, whose pathophysiology has been linked to the neuroinflammatory process. The increased activity of the Nod-like receptor pyrin containing protein 3 (NLRP3) inflammasome, an intracellular multiprotein complex, is intrinsically implicated in neuroinflammation by promoting the maturation and release of proinflammatory cytokines such as interleukin (IL)-1β and IL-18. Interestingly, individuals suffering from MDD have higher expression of NLRP3 inflammasome components and proinflammatory cytokines when compared to healthy individuals. In part, intense activation of the inflammasome may be related to autophagic impairment. Noteworthy, some conventional antidepressants induce autophagy, resulting in less activation of the NLRP3 inflammasome. In addition, the fast-acting antidepressant ketamine, some bioactive compounds and physical exercise have also been shown to have anti-inflammatory properties via inflammasome inhibition. Therefore, it is suggested that modulation of inflammasome-driven pathways may have an antidepressant effect. Here, we review the role of the NLRP3 inflammasome in the pathogenesis of MDD, highlighting that pathways related to its priming and activation are potential therapeutic targets for the treatment of MDD. Full article

(This article belongs to the Special Issue New Insights into Inflammasomes)

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21 pages, 2003 KiB

Open AccessReview

Does Pyroptosis Play a Role in Inflammasome-Related Disorders?

by Jiajia Zhang and Stefan Wirtz

Int. J. Mol. Sci. 2022, 23(18), 10453; https://doi.org/10.3390/ijms231810453 - 09 Sep 2022

Cited by 7 | Viewed by 4366

Abstract

Inflammasomes are multiprotein complexes orchestrating intracellular recognition of endogenous and exogenous stimuli, cellular homeostasis, and cell death. Upon sensing of certain stimuli, inflammasomes typically activate inflammatory caspases that promote the production and release of the proinflammatory cytokines IL-1β, IL-1α, and IL-18 and induce a type of inflammatory cell death known as “pyroptosis”. Pyroptosis is an important form of regulated cell death executed by gasdermin proteins, which is largely different from apoptosis and necrosis. Recently, several signaling pathways driving pyroptotic cell death, including canonical and noncanonical inflammasome activation, as well as caspase-3-dependent pathways, have been reported. While much evidence exists that pyroptosis is involved in the development of several inflammatory diseases, its contribution to inflammasome-related disorders (IRDs) has not been fully clarified. This article reviews molecular mechanisms leading to pyroptosis, and attempts to provide evidence for its possible role in inflammasome-related disorders, including NLR pyrin domain containing 3 (NLRP3) inflammasome disease, NLR containing a caspase recruitment domain 4 (NLRC4) inflammasome disease, and pyrin inflammasome disease. Although the specific mechanism needs further investigations, these studies have uncovered the role of pyroptosis in inflammasome-related disorders and may open new avenues for future therapeutic interventions. Full article

(This article belongs to the Special Issue New Insights into Inflammasomes)

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