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Regulatory Roles of Inflammasomes in Human Diseases
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Regulatory Roles of Inflammasomes in Human Diseases

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

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 18519

Special Issue Editors

Dr. Young-Su Yi

E-Mail Website
Guest Editor
Department of Life Sciences, Kyonggi University, Suwon 16227, Republic of Korea
Interests: inflammation; inflammatory/autoimmune diseases; non-canonical inflammasomes; macrophage; anti-inflammatory therapeutics, signaling transduction; immunology; molecular biology; biochemistry
Special Issues, Collections and Topics in MDPI journals
Dr. Miyong Yun

E-Mail Website
Co-Guest Editor
Faculty of Molecular Biology, Sejong University, Seoul 05006, Republic of Korea
Interests: zerumbone; ETBF; BFT; inflammation; nf-κb
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Inflammasomes are intracellular protein complexes comprising intracellular pattern recognition receptors and other inflammatory molecules and play a pivotal role in the inflammatory responses. Inflammasomes are activated in response to a variety of pathogens and danger signals, resulting in caspase-1-dependent maturation and secretion of IL-1β and IL-18 as well as gsdermin D-mediated pyroptosis, an inflammatory cell death. Previous studies have uncovered the activation of inflammasomes in the inflammatory responses and their dysregulation in many human diseases; therefore, inflammasomes have been considered as critical drug targets to treat a wide range of human diseases.

This Special Issue welcomes original research, reviews, and perspectives with a focus on but not limited to the mechanisms of inflammasome regulation, the role of inflammasome in disease pathogenesis, identification and validation of novel molecules modulating inflammasome activation, development of inflammasome-targeting strategies, and inflammasome-targeted therapeutics.

Dr. Young-Su Yi
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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Published Papers (7 papers)

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Editorial

Jump to: Research, Review

3 pages, 159 KiB  
Editorial
Editorial of Special Issue “Regulatory Roles of Inflammasomes in Human Diseases”
by Young-Su Yi and Miyong Yun
Int. J. Mol. Sci. 2021, 22(6), 3008; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063008 - 16 Mar 2021
Cited by 1 | Viewed by 1323
Abstract
Inflammation is an innate immunity protecting the body from pathogens and cellular damages and comprises two steps; 1) priming (preparatory step) and triggering (activation step). The key feature of the triggering step is the activation of inflammasomes that are intracellular protein complexes consisting [...] Read more.
Inflammation is an innate immunity protecting the body from pathogens and cellular damages and comprises two steps; 1) priming (preparatory step) and triggering (activation step). The key feature of the triggering step is the activation of inflammasomes that are intracellular protein complexes consisting of pattern recognition receptors and inflammatory molecules. Inflammasomes are activated in response to various ligands, leading to the caspase-1-mediated maturation and secretion of pro-inflammatory cytokines, IL-1β and IL-18 and the gasdermin D-mediated pyroptosis, an inflammatory form of cell death. Previous studies have demonstrated that inflammasome activation is a key determinant of inflammatory responses and many human diseases; therefore, inflammasomes have been attracted much attention as critical drug targets to prevent and treat various human diseases. Full article
(This article belongs to the Special Issue Regulatory Roles of Inflammasomes in Human Diseases)

Research

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17 pages, 3781 KiB  
Article
ANP and BNP Exert Anti-Inflammatory Action via NPR-1/cGMP Axis by Interfering with Canonical, Non-Canonical, and Alternative Routes of Inflammasome Activation in Human THP1 Cells
by Letizia Mezzasoma, Vincenzo Nicola Talesa, Rita Romani and Ilaria Bellezza
Int. J. Mol. Sci. 2021, 22(1), 24; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010024 - 22 Dec 2020
Cited by 18 | Viewed by 2535
Abstract
Dysregulated inflammasome activation and interleukin (IL)-1β production are associated with several inflammatory disorders. Three different routes can lead to inflammasome activation: a canonical two-step, a non-canonical Caspase-4/5- and Gasdermin D-dependent, and an alternative Caspase-8-mediated pathway. Natriuretic Peptides (NPs), Atrial Natriuretic Peptide (ANP) and [...] Read more.
Dysregulated inflammasome activation and interleukin (IL)-1β production are associated with several inflammatory disorders. Three different routes can lead to inflammasome activation: a canonical two-step, a non-canonical Caspase-4/5- and Gasdermin D-dependent, and an alternative Caspase-8-mediated pathway. Natriuretic Peptides (NPs), Atrial Natriuretic Peptide (ANP) and B-type Natriuretic Peptide (BNP), binding to Natriuretic Peptide Receptor-1 (NPR-1), signal by increasing cGMP (cyclic guanosine monophosphate) levels that, in turn, stimulate cGMP-dependent protein kinase-I (PKG-I). We previously demonstrated that, by counteracting inflammasome activation, NPs inhibit IL-1β secretion. Here we aimed to decipher the molecular mechanism underlying NPs effects on THP-1 cells stimulated with lipopolysaccharide (LPS) + ATP. Involvement of cGMP and PKG-I were assessed pre-treating THP-1 cells with the membrane-permeable analogue, 8-Br-cGMP, and the specific inhibitor KT-5823, respectively. We found that NPs, by activating NPR-1/cGMP/PKG-I axis, lead to phosphorylation of NLRP3 at Ser295 and to inflammasome platform disassembly. Moreover, by increasing intracellular cGMP levels and activating phosphodiesterases, NPs interfere with both Gasdermin D and Caspase-8 cleavage, indicating that they disturb non-canonical and alternative routes of inflammasome activation. These results showed that ANP and BNP anti-inflammatory and immunomodulatory actions may involve the inhibition of all the known routes of inflammasome activation. Thus, NPs might be proposed for the treatment of the plethora of diseases caused by a dysregulated inflammasome activation. Full article
(This article belongs to the Special Issue Regulatory Roles of Inflammasomes in Human Diseases)
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12 pages, 1095 KiB  
Article
ASC, IL-18 and Galectin-3 as Biomarkers of Non-Alcoholic Steatohepatitis: A Proof of Concept Study
by Brianna Cyr, Robert W. Keane and Juan Pablo de Rivero Vaccari
Int. J. Mol. Sci. 2020, 21(22), 8580; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228580 - 13 Nov 2020
Cited by 18 | Viewed by 2114
Abstract
Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease that is growing in prevalence. Symptoms of NASH become apparent when the disease has progressed significantly. Thus, there is a need to identify biomarkers of NASH in order to detect the [...] Read more.
Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease that is growing in prevalence. Symptoms of NASH become apparent when the disease has progressed significantly. Thus, there is a need to identify biomarkers of NASH in order to detect the disease earlier and to monitor disease severity. The inflammasome has been shown to play a role in liver diseases. Here, we performed a proof of concept study of biomarker analyses (cut-off points, positive and negative predictive values, receiver operating characteristic (ROC) curves, and likelihood ratios) on the serum of patients with NASH and healthy controls on apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), interleukin (IL)-18, Galectin-3 (Gal-3), and C-reactive protein (CRP). ASC, IL-18, and Gal-3 were elevated in the serum of NASH patients when compared to controls. The area under the curve (AUC) for ASC was the highest (0.7317) with an accuracy of 68%, followed by IL-18 (0.7036) with an accuracy of 66% and Gal-3 (0.6891) with an accuracy of 61%. Moreover, we then fit a stepwise multivariate logistic regression model using ASC, IL-18, and Gal-3 to determine the probability of patients having a NASH diagnosis, which resulted in an AUC of 0.71 and an accuracy of 79%, indicating that combining these biomarkers increases their diagnostic potential for NASH. These results indicate that ASC, IL-18, and Gal-3 are reliable biomarkers of NASH and that combining these analytes increases the biomarker potential of these proteins. Full article
(This article belongs to the Special Issue Regulatory Roles of Inflammasomes in Human Diseases)
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11 pages, 3385 KiB  
Article
Erythropoietin Ameliorates Ischemia/Reperfusion-Induced Acute Kidney Injury via Inflammasome Suppression in Mice
by Jihye Kwak, Jin Hyun Kim, Ha Nee Jang, Myeong Hee Jung, Hyun Seop Cho, Se-Ho Chang and Hyun-Jung Kim
Int. J. Mol. Sci. 2020, 21(10), 3453; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103453 - 13 May 2020
Cited by 24 | Viewed by 3294
Abstract
Acute kidney injury (AKI) is the most common condition in hospitalized patients. As ischemia/reperfusion-induced AKI (IR-AKI) is as a major contributor to end-stage disease, an effective therapeutic intervention for IR-AKI is imperative. Erythropoietin (EPO) is a potent stimulator of erythroid progenitor cells and [...] Read more.
Acute kidney injury (AKI) is the most common condition in hospitalized patients. As ischemia/reperfusion-induced AKI (IR-AKI) is as a major contributor to end-stage disease, an effective therapeutic intervention for IR-AKI is imperative. Erythropoietin (EPO) is a potent stimulator of erythroid progenitor cells and is significantly upregulated during hypoxia. Here, we investigated the renoprotective effects of EPO in an IR-AKI mouse model. Mice were assigned to sham, EPO only, and IR only groups, and the IR group was treated with EPO prior to injury. EPO was administered twice at 30 min prior to bilateral renal artery occlusion, and 5 min before reperfusion, with all mice sacrificed 24 h after IR-AKI. The serum was harvested for renal functional measurements. The kidneys were subjected to histological evaluation, and the biochemical changes associated with renal injury were assessed. EPO significantly attenuated the renal dysfunction associated with IR-AKI, as well as tissue injury. Apoptotic cell death and oxidative stress were significantly reduced in EPO-treated mice. Macrophage infiltration and expression of ICAM-1 and MCP-1 were also significantly reduced in EPO-treated mice. Furthermore, the expression of inflammasome-related factors (NLRP1, NLRP3, and caspase-1 cleavage), via the activation of the COX-2 and NF-κB signaling pathways were significantly reduced following EPO treatment. To our knowledge, this is the first study to demonstrate that inflammasome-mediated inflammation might be a potential target of EPO as a treatment for ischemic AKI. Full article
(This article belongs to the Special Issue Regulatory Roles of Inflammasomes in Human Diseases)
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Review

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18 pages, 612 KiB  
Review
Flavonoids: Nutraceuticals for Rheumatic Diseases via Targeting of Inflammasome Activation
by Young-Su Yi
Int. J. Mol. Sci. 2021, 22(2), 488; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020488 - 06 Jan 2021
Cited by 13 | Viewed by 2479
Abstract
Inflammation, an innate immune response that prevents cellular damage caused by pathogens, consists of two successive mechanisms, namely priming and triggering. While priming is an inflammation-preparation step, triggering is an inflammation-activation step, and the central feature of triggering is the activation of inflammasomes [...] Read more.
Inflammation, an innate immune response that prevents cellular damage caused by pathogens, consists of two successive mechanisms, namely priming and triggering. While priming is an inflammation-preparation step, triggering is an inflammation-activation step, and the central feature of triggering is the activation of inflammasomes and intracellular inflammatory protein complexes. Flavonoids are natural phenolic compounds predominantly present in plants, fruits, and vegetables and are known to possess strong anti-inflammatory activities. The anti-inflammatory activity of flavonoids has long been demonstrated, with the main focus on the priming mechanisms, while increasing numbers of recent studies have redirected the research focus on the triggering step, and studies have reported that flavonoids inhibit inflammatory responses and diseases by targeting inflammasome activation. Rheumatic diseases are systemic inflammatory and autoimmune diseases that primarily affect joints and connective tissues, and they are associated with numerous deleterious effects. Here, we discuss the emerging literature on the ameliorative role of flavonoids targeting inflammasome activation in inflammatory rheumatic diseases. Full article
(This article belongs to the Special Issue Regulatory Roles of Inflammasomes in Human Diseases)
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24 pages, 2300 KiB  
Review
Contradictory Effects of NLRP3 Inflammasome Regulatory Mechanisms in Colitis
by Kohei Wagatsuma and Hiroshi Nakase
Int. J. Mol. Sci. 2020, 21(21), 8145; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218145 - 30 Oct 2020
Cited by 15 | Viewed by 3233
Abstract
The inflammasome is an intracellular molecular complex, which is mainly involved in innate immunity. Inflammasomes are formed in response to danger signals, associated with infection and injury, and mainly regulate the secretion of interleukin-1β and interleukin-18. Inflammasome dysregulation is known to be associated [...] Read more.
The inflammasome is an intracellular molecular complex, which is mainly involved in innate immunity. Inflammasomes are formed in response to danger signals, associated with infection and injury, and mainly regulate the secretion of interleukin-1β and interleukin-18. Inflammasome dysregulation is known to be associated with various diseases and conditions, and its regulatory mechanisms have become of great interest in recent years. In the colon, inflammasomes have been reported to be associated with autophagy and the microbiota, and their dysregulation contributes to colitis and. However, the detailed role of inflammasomes in inflammatory bowel disease is still under debate because the mechanisms that regulate the inflammasome are complex and the inflammasome components and cytokines show seemingly contradictory multiple effects. Herein, we comprehensively review the literature on inflammasome functioning in the colon and describe the complex interactions of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome components with inflammatory cytokines, autophagy, and the microbiota in experimental colitis models and patients with inflammatory bowel disease. Full article
(This article belongs to the Special Issue Regulatory Roles of Inflammasomes in Human Diseases)
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11 pages, 1601 KiB  
Review
Caspase-11 Non-Canonical Inflammasome: Emerging Activator and Regulator of Infection-Mediated Inflammatory Responses
by Young-Su Yi
Int. J. Mol. Sci. 2020, 21(8), 2736; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082736 - 15 Apr 2020
Cited by 34 | Viewed by 2894
Abstract
Inflammation is a body’s protective mechanism to eliminate invading pathogens and cellular damaging signals. The inflammatory response consists of two main consecutive steps—a priming step preparing the inflammatory responses and a triggering step boosting the inflammatory responses. The main feature of the triggering [...] Read more.
Inflammation is a body’s protective mechanism to eliminate invading pathogens and cellular damaging signals. The inflammatory response consists of two main consecutive steps—a priming step preparing the inflammatory responses and a triggering step boosting the inflammatory responses. The main feature of the triggering step is the activation of the inflammasome, an intracellular multiprotein complex facilitating the inflammatory responses. The regulatory roles of ‘canonical’ inflammasomes in the inflammatory responses and diseases have been largely investigated, so far. New types of inflammasomes have been recently discovered and named as ‘non-canonical’ inflammasomes since their roles to induce inflammatory responses are similar to those of canonical inflammasomes, however, the stimulating ligands and the underlying mechanisms are different. Therefore, a growing number of studies have actively investigated the novel roles of non-canonical inflammasomes in inflammatory responses and diseases. This review summarizes and discusses the recent studies exploring the regulatory roles of caspase-11 non-canonical inflammasome during the inflammatory responses and provides insight into the development of novel therapeutics for infectious and inflammatory diseases by targeting caspase-11 non-canonical inflammasome. Full article
(This article belongs to the Special Issue Regulatory Roles of Inflammasomes in Human Diseases)
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