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Inflammasome Inhibitors

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 84201

Special Issue Editor


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Guest Editor
Department of Drug Science and Technology, University of Turin, 10125 Torino, Italy
Interests: drug discovery, synthesis and structure-activity relationships of biologically active compounds; design and synthesis of multi-target drugs and NLRP3 ligands for the treatment of chronic inflammatory, neurodegenerative and autoimmune diseases. Protein targeting chimaeras (PROTACs)

Special Issue Information

Dear Colleagues,

Inflammasomes are intracellular multiprotein complexes that play a fundamental role in the immune system. Since the discovery of the NLRP3 inflammasome by Jürg Tschopp’s group in 2002, the inflammasome has attracted a great deal of interest because of its intriguing biochemical properties and potential role as a drug target.

Over the last decade, altered NLRP3 signaling has been associated to a range of different pathogenic conditions. Autoinflammatory syndromes, collectively known as cryopyrinopathies (CAPS), were initially identified as being a direct result of gain of function mutations in the NLRP3 gene. Afterwards, NLRP3 overexpression/overactivation was detected in many peripheral and central nervous system diseases, such as arthritis, gout, atherosclerosis, Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. More recently, a great deal of effort has been dedicated to the elucidation of NLRP3 signaling and the discovery of ligands that can inhibit its activation; more than 1300 scientific reports citing NLRP3 have been published over the last year. The main aim of this Special Issue on “Inflammasome Inhibitors” is to collect the latest developments in the design and pharmacological characterization of new NLRP3 ligands. Contributions to this issue, in the form of original research and review articles, are particularly welcome.

Prof. Dr. Massimo Bertinaria
Guest Editor

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Keywords

  • NLRP3 inflammasome
  • NLRP3 inhibitors
  • IL-1β blockers
  • Pyroptosis
  • Inflammation

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Published Papers (16 papers)

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Editorial

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6 pages, 216 KiB  
Editorial
Inflammasome Inhibitors
by Massimo Bertinaria
Molecules 2021, 26(22), 6912; https://doi.org/10.3390/molecules26226912 - 16 Nov 2021
Cited by 2 | Viewed by 1788
Abstract
In recent years, the interplay between the activation of the immune system, the development of chronic inflammation and the onset and progression of many different diseases has been studied extensively [...] Full article
(This article belongs to the Special Issue Inflammasome Inhibitors)

Research

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35 pages, 6053 KiB  
Article
Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor
by Simone Gastaldi, Valentina Boscaro, Eleonora Gianquinto, Christina F. Sandall, Marta Giorgis, Elisabetta Marini, Federica Blua, Margherita Gallicchio, Francesca Spyrakis, Justin A. MacDonald and Massimo Bertinaria
Molecules 2021, 26(13), 3975; https://doi.org/10.3390/molecules26133975 - 29 Jun 2021
Cited by 13 | Viewed by 3915
Abstract
In the search for new chemical scaffolds able to afford NLRP3 inflammasome inhibitors, we used a pharmacophore-hybridization strategy by combining the structure of the acrylic acid derivative INF39 with the 1-(piperidin-4-yl)1,3-dihydro-2H-benzo[d]imidazole-2-one substructure present in HS203873, a recently identified NLRP3 binder. A [...] Read more.
In the search for new chemical scaffolds able to afford NLRP3 inflammasome inhibitors, we used a pharmacophore-hybridization strategy by combining the structure of the acrylic acid derivative INF39 with the 1-(piperidin-4-yl)1,3-dihydro-2H-benzo[d]imidazole-2-one substructure present in HS203873, a recently identified NLRP3 binder. A series of differently modulated benzo[d]imidazole-2-one derivatives were designed and synthesised. The obtained compounds were screened in vitro to test their ability to inhibit NLRP3-dependent pyroptosis and IL-1β release in PMA-differentiated THP-1 cells stimulated with LPS/ATP. The selected compounds were evaluated for their ability to reduce the ATPase activity of human recombinant NLRP3 using a newly developed assay. From this screening, compounds 9, 13 and 18, able to concentration-dependently inhibit IL-1β release in LPS/ATP-stimulated human macrophages, emerged as the most promising NLRP3 inhibitors of the series. Computational simulations were applied for building the first complete model of the NLRP3 inactive state and for identifying possible binding sites available to the tested compounds. The analyses led us to suggest a mechanism of protein–ligand binding that might explain the activity of the compounds. Full article
(This article belongs to the Special Issue Inflammasome Inhibitors)
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12 pages, 2739 KiB  
Article
Preservation of Contractile Reserve and Diastolic Function by Inhibiting the NLRP3 Inflammasome with OLT1177® (Dapansutrile) in a Mouse Model of Severe Ischemic Cardiomyopathy Due to Non-Reperfused Anterior Wall Myocardial Infarction
by Joseph Aliaga, Aldo Bonaventura, Eleonora Mezzaroma, Yogesh Dhakal, Adolfo Gabriele Mauro, Antonio Abbate and Stefano Toldo
Molecules 2021, 26(12), 3534; https://doi.org/10.3390/molecules26123534 - 9 Jun 2021
Cited by 29 | Viewed by 3406
Abstract
Interleukin-1β (IL-1β), a product of the NLRP3 inflammasome, modulates cardiac contractility and diastolic function. We proposed that OLT1177® (dapansutrile), a novel NLRP3 inhibitor, could preserve contractile reserve and diastolic function after myocardial infarction (MI). We used an experimental murine model of severe [...] Read more.
Interleukin-1β (IL-1β), a product of the NLRP3 inflammasome, modulates cardiac contractility and diastolic function. We proposed that OLT1177® (dapansutrile), a novel NLRP3 inhibitor, could preserve contractile reserve and diastolic function after myocardial infarction (MI). We used an experimental murine model of severe ischemic cardiomyopathy through the ligation of the left coronary artery without reperfusion, and after 7 days randomly assigned mice showing large anterior MI (>4 akinetic segments), increased left ventricular (LV) dimensions ([LVEDD] > 4.4 mm), and reduced function (LV ejection fraction < 40%) to a diet that was enriched with OLT1177® admixed with the chow in the diet at 3.75 g/kg (Group 1 [n = 10]) or 7.5 g/kg (Group 2 [n = 9]), or a standard diet as the no-treatment control group (Group 3 [n = 10]) for 9 weeks. We measured the cardiac function and contractile reserve with an isoproterenol challenge, and the diastolic function with cardiac catheterization at 10 weeks following the MI surgery. When compared with the control (Group 3), the mice treated with OLT1177 (Group 1 and 2) showed significantly greater preservation of their contractile reserve (the percent increase in the left ventricular ejection fraction [LVEF] after the isoproterenol challenge was +33 ± 11% and +40 ± 6% vs. +9 ± 7% in the standard diet; p < 0.05 and p < 0.005 for Group 1 and 2, respectively) and of diastolic function measured as the lower left ventricular end-diastolic pressure (3.2 ± 0.5 mmHg or 4.5 ± 0.5 mmHg vs. 10.0 ± 1.6 mmHg; p < 0.005 and p < 0.009 respectively). No differences were noted between the resting LVEF of the MI groups. These effects were independent of the effects on the ventricular remodeling after MI. NLRP3 inflammasome inhibition with OLT1177® can preserve β-adrenergic responsiveness and prevent left ventricular diastolic dysfunction in a large non-reperfused anterior MI mouse model. OLT1177® could therefore be used to prevent the development of heart failure in patients with ischemic cardiomyopathy. Full article
(This article belongs to the Special Issue Inflammasome Inhibitors)
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13 pages, 3237 KiB  
Article
Loganin Alleviates Gout Inflammation by Suppressing NLRP3 Inflammasome Activation and Mitochondrial Damage
by Nuri Choi, Gabsik Yang, Joo Hyeon Jang, Han Chang Kang, Yong-Yeon Cho, Hye Suk Lee and Joo Young Lee
Molecules 2021, 26(4), 1071; https://doi.org/10.3390/molecules26041071 - 18 Feb 2021
Cited by 31 | Viewed by 4116
Abstract
Gout is a type of inflammatory arthritis caused by the deposition of monosodium uric acid (MSU) crystals in tissues. The etiology of gout is directly linked to the NLRP3 inflammasome, since MSU crystals are NLRP3 inflammasome activators. Therefore, we decided to search for [...] Read more.
Gout is a type of inflammatory arthritis caused by the deposition of monosodium uric acid (MSU) crystals in tissues. The etiology of gout is directly linked to the NLRP3 inflammasome, since MSU crystals are NLRP3 inflammasome activators. Therefore, we decided to search for a small-molecule inhibitor of the NLRP3 inflammasome for the prevention of gout inflammation. We found that loganin suppressed MSU crystals-induced caspase-1 (p20) and interleukin (IL)-1β production and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) specks formation in mouse primary macrophages, showing its ability to inhibit the NLRP3 inflammasome. In an air pouch inflammation model, oral administration of loganin to mice prevented MSU crystals-induced production of mature IL-1β and IL-18 in air pouch exudates, resulting in decreased neutrophil recruitment. Furthermore, oral administration of loganin suppressed MSU crystals-induced gout inflammation in a mouse foot gout model, which was accompanied by the inhibition of the NLRP3 inflammasome. Loganin blocked de novo synthesis of mitochondrial DNA in air pouches and foot tissues injected with MSU crystals. Consistently, loganin prevented MSU crystals-induced mitochondrial damage in macrophages, as it increased mitochondrial membrane potential and decreased the amount of mitochondrial reactive oxygen species. These data demonstrate that loganin suppresses NLRP3 inflammasome activation by inhibiting mitochondrial stress. These results suggest a novel pharmacological strategy to prevent gout inflammation by blocking NLRP3 inflammasome activation and mitochondrial dysfunction. Full article
(This article belongs to the Special Issue Inflammasome Inhibitors)
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13 pages, 3163 KiB  
Article
Alpha-Lipoic Acid Plays a Role in Endometriosis: New Evidence on Inflammasome-Mediated Interleukin Production, Cellular Adhesion and Invasion
by Fiorella Di Nicuolo, Roberta Castellani, Alessandra De Cicco Nardone, Greta Barbaro, Carmela Paciullo, Alfredo Pontecorvi, Giovanni Scambia and Nicoletta Di Simone
Molecules 2021, 26(2), 288; https://doi.org/10.3390/molecules26020288 - 8 Jan 2021
Cited by 15 | Viewed by 6821
Abstract
Endometriosis is an estrogen-linked gynecological disease defined by the presence of endometrial tissue on extrauterine sites where it forms invasive lesions. Alterations in estrogen-mediated cellular signaling seems to have an essential role in the pathogenesis of endometriosis. Higher estrogen receptor (ER)-β levels and [...] Read more.
Endometriosis is an estrogen-linked gynecological disease defined by the presence of endometrial tissue on extrauterine sites where it forms invasive lesions. Alterations in estrogen-mediated cellular signaling seems to have an essential role in the pathogenesis of endometriosis. Higher estrogen receptor (ER)-β levels and enhanced ER-β activity were detected in endometriotic tissues. It is well known that ER-β interacts with components of the cytoplasmic inflammasome-3 (NALP-3), the NALP-3 activation increases interleukin (IL)-1β and IL-18, enhancing cellular adhesion and proliferation. Otherwise, the inhibition of ER-β activity suppresses the ectopic lesions growth. The present study aims to investigate the potential effect of α-lipoic acid (ALA) on NALP-3 and ER-β expression using a western blot analysis, NALP-3-induced cytokines production by ELISA, migration and invasion of immortalized epithelial (12Z) and stromal endometriotic cells (22B) using a 3D culture invasion assay, and matrix-metalloprotease (MMPs) activity using gelatin zymography. ALA significantly reduces ER-β, NALP-3 protein expression/activity and the secretion of IL-1β and IL-18 in both 12Z and 22B cells. ALA treatment reduces cellular adhesion and invasion via a lower expression of adhesion molecules and MMPs activities. These results provide convincing evidence that ALA might inhibit endometriosis progression. Full article
(This article belongs to the Special Issue Inflammasome Inhibitors)
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17 pages, 4399 KiB  
Article
Chalcones Display Anti-NLRP3 Inflammasome Activity in Macrophages through Inhibition of Both Priming and Activation Steps—Structure-Activity-Relationship and Mechanism Studies
by Wohn-Jenn Leu, Jung-Chun Chu, Jui-Ling Hsu, Chi-Min Du, Yi-Huei Jiang, Lih-Ching Hsu, Wei-Jan Huang and Jih-Hwa Guh
Molecules 2020, 25(24), 5960; https://doi.org/10.3390/molecules25245960 - 16 Dec 2020
Cited by 9 | Viewed by 2715
Abstract
Chalcones are responsible for biological activity throughout fruits, vegetables, and medicinal plants in preventing and treating a variety of inflammation-related diseases. However, their structure-activity relationship (SAR) in inhibiting inflammasome activation has not been explored. We synthesized numerous chalcones and determined their SAR on [...] Read more.
Chalcones are responsible for biological activity throughout fruits, vegetables, and medicinal plants in preventing and treating a variety of inflammation-related diseases. However, their structure-activity relationship (SAR) in inhibiting inflammasome activation has not been explored. We synthesized numerous chalcones and determined their SAR on lipopolysaccharide (LPS)-primed ATP-induced NLRP3 inflammasome activation. 11Cha1 displayed good inhibitory activity on release reaction of caspase-1, IL-1β, and IL-18. It significantly inhibited LPS-induced phosphorylation and proteolytic degradation of IĸB-α and nuclear translocation of NF-ĸB, but had little effect on mitogen-activated protein kinases (MAPKs) activities. Furthermore, 11Cha1 blocked LPS-induced up-regulation of NLRP3, pro-caspase-1, ASC, IL-18, and IL-1β, indicating the suppression on priming step of inflammasome activation. ASC dimerization and oligomerization are considered to be direct evidence for inflammasome activation. 11Cha1 profoundly inhibited ATP-induced formation of ASC dimers, trimers, and oligomers, and the assembly of ASC, pro-caspase-1, and NLRP3 in inflammasome formation. Decrease of intracellular K+ levels is the common cellular activity elicited by all NLRP3 inflammasome activators. 11Cha1 substantially diminished ATP-mediated K+ efflux, confirming the anti-NLRP3 inflammasome activity of 11Cha1. In summary, the SAR of chalcone derivatives in anti-inflammasome activities was examined. Besides, 11Cha1 inhibited both priming and activation steps of NLRP3 inflammasome activation. It inhibited NF-ĸB activation and subsequently suppressed the up-regulation of NLRP3 inflammasome components including NLRP3, ASC, pro-caspase-1, pro-IL-18, and pro-IL-1β. Next, 11Cha1 blocked ATP-mediated K+ efflux and suppressed the assembly and activation of NLRP3 inflammasome, leading to the inhibition of caspase-1 activation and proteolytic cleavage, maturation, and secretion of IL-1β and IL-18. Full article
(This article belongs to the Special Issue Inflammasome Inhibitors)
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16 pages, 1160 KiB  
Article
The Inhibition of NLRP3 Inflammasome and IL-6 Production by Hibiscus noldeae Baker f. Derived Constituents Provides a Link to Its Anti-Inflammatory Therapeutic Potentials
by Jean Claude Didelot Tomani, Vedaste Kagisha, Alembert Tiabou Tchinda, Olivia Jansen, Allison Ledoux, Luc Vanhamme, Michel Frederich, Raymond Muganga and Jacob Souopgui
Molecules 2020, 25(20), 4693; https://doi.org/10.3390/molecules25204693 - 14 Oct 2020
Cited by 18 | Viewed by 3440
Abstract
The activation of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome and/or its components is associated with the physio-pathogenesis of many respiratory diseases including asthma, COPD (chronic obstructive pulmonary disease), SARS Cov-2 (severe acute respiratory syndrome coronavirus 2), and in several autoimmune [...] Read more.
The activation of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome and/or its components is associated with the physio-pathogenesis of many respiratory diseases including asthma, COPD (chronic obstructive pulmonary disease), SARS Cov-2 (severe acute respiratory syndrome coronavirus 2), and in several autoimmune diseases. Hibiscus noldeae Baker f. has been widely reported to be traditionally used in the treatment of different ailments, some of which are of inflammatory background such as asthma, wounds, headache, etc. However, the claims have not been supported by evidence at the molecular and functional levels. Here, we report on the bio-guided fractionation of H. noldeae and assessment of the inhibitory properties of some fractions and purified compounds on NLRP3 inflammasome and Interleukin 6 (IL-6). The activation of the NLRP3 inflammasome was determined by detecting the activity of caspase-1 and the production of Interleukin 1β (IL-1β) in Lipopolysaccharide (LPS) and ATP-stimulated Tamm-Horsfall Protein 1 (THP-1) macrophages, while the production of IL-6 was studied in LPS-stimulated RAW264.7 mouse macrophages. It was observed that hexane and ethyl acetate fractions of the crude extract of the aerial parts of H. noldeae, as well as caffeic acid, isoquercetin, and ER2.4 and ER2.7 fractions revealed significant inhibitory effects on Caspase-1 activities, and on IL-1β and IL-6 production. The ER2.4 and ER2.7 fractions downregulated the production of IL-1β and IL-6, in a similar range as the caspase-1 inhibitor AC-YVAD-CHO and the drug Dexamethasone, both used as controls, respectively. Overall, our work does provide the very first scientific based evidence for Hibiscus noldeae anti-inflammatory effects and widespread use by traditional healers in Rwanda for a variety of ailments. Full article
(This article belongs to the Special Issue Inflammasome Inhibitors)
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Review

Jump to: Editorial, Research

49 pages, 1403 KiB  
Review
Promise of the NLRP3 Inflammasome Inhibitors in In Vivo Disease Models
by Biswadeep Das, Chayna Sarkar, Vikram Singh Rawat, Deepjyoti Kalita, Sangeeta Deka and Akash Agnihotri
Molecules 2021, 26(16), 4996; https://doi.org/10.3390/molecules26164996 - 18 Aug 2021
Cited by 22 | Viewed by 5277
Abstract
Nucleotide-binding oligomerization domain NOD-like receptors (NLRs) are conserved cytosolic pattern recognition receptors (PRRs) that track the intracellular milieu for the existence of infection, disease-causing microbes, as well as metabolic distresses. The NLRP3 inflammasome agglomerates are consequent to sensing a wide spectrum of pathogen-associated [...] Read more.
Nucleotide-binding oligomerization domain NOD-like receptors (NLRs) are conserved cytosolic pattern recognition receptors (PRRs) that track the intracellular milieu for the existence of infection, disease-causing microbes, as well as metabolic distresses. The NLRP3 inflammasome agglomerates are consequent to sensing a wide spectrum of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). Certain members of the NLR family have been documented to lump into multimolecular conglomerates called inflammasomes, which are inherently linked to stimulation of the cysteine protease caspase-1. Following activation, caspase-1 severs the proinflammatory cytokines interleukin (IL)-1β and IL-18 to their biologically active forms, with consequent commencement of caspase-1-associated pyroptosis. This type of cell death by pyroptosis epitomizes a leading pathway of inflammation. Accumulating scientific documentation has recorded overstimulation of NLRP3 (NOD-like receptor protein 3) inflammasome involvement in a wide array of inflammatory conditions. IL-1β is an archetypic inflammatory cytokine implicated in multiple types of inflammatory maladies. Approaches to impede IL-1β’s actions are possible, and their therapeutic effects have been clinically demonstrated; nevertheless, such strategies are associated with certain constraints. For instance, treatments that focus on systemically negating IL-1β (i.e., anakinra, rilonacept, and canakinumab) have been reported to result in an escalated peril of infections. Therefore, given the therapeutic promise of an NLRP3 inhibitor, the concerted escalated venture of the scientific sorority in the advancement of small molecules focusing on direct NLRP3 inflammasome inhibition is quite predictable. Full article
(This article belongs to the Special Issue Inflammasome Inhibitors)
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18 pages, 1057 KiB  
Review
Inflammasome Regulation: Therapeutic Potential for Inflammatory Bowel Disease
by Qiuyun Xu, Xiaorong Zhou, Warren Strober and Liming Mao
Molecules 2021, 26(6), 1725; https://doi.org/10.3390/molecules26061725 - 19 Mar 2021
Cited by 19 | Viewed by 4499
Abstract
Inflammasomes are multiprotein complexes formed to regulate the maturation of pro-inflammatory caspases, in response to intracellular or extracellular stimulants. Accumulating studies showed that the inflammasomes are implicated in the pathogenesis of inflammatory bowel disease (IBD), although their activation is not a decisive factor [...] Read more.
Inflammasomes are multiprotein complexes formed to regulate the maturation of pro-inflammatory caspases, in response to intracellular or extracellular stimulants. Accumulating studies showed that the inflammasomes are implicated in the pathogenesis of inflammatory bowel disease (IBD), although their activation is not a decisive factor for the development of IBD. Inflammasomes and related cytokines play an important role in the maintenance of gut immune homeostasis, while its overactivation might induce excess immune responses and consequently cause tissue damage in the gut. Emerging studies provide evidence that some genetic abnormalities might induce enhanced NLRP3 inflammasome activation and cause colitis. In these cases, the colonic inflammation can be ameliorated by blocking NLRP3 activation or its downstream cytokine IL-1β. A number of natural products were shown to play a role in preventing colon inflammation in various experimental colitis models. On the other hand, lack of inflammasome function also causes intestinal abnormalities. Thus, an appropriate regulation of inflammasomes might be a promising therapeutic strategy for IBD intervention. This review aims at summarizing the main findings in these studies and provide an outline for further studies that might contribute to our understanding of the role of inflammasomes in the pathogenesis and therapeutic treatment of IBD. Full article
(This article belongs to the Special Issue Inflammasome Inhibitors)
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24 pages, 3061 KiB  
Review
Techniques to Study Inflammasome Activation and Inhibition by Small Molecules
by Diego Angosto-Bazarra, Cristina Molina-López, Alejandro Peñín-Franch, Laura Hurtado-Navarro and Pablo Pelegrín
Molecules 2021, 26(6), 1704; https://doi.org/10.3390/molecules26061704 - 18 Mar 2021
Cited by 13 | Viewed by 4949
Abstract
Inflammasomes are immune cytosolic oligomers involved in the initiation and progression of multiple pathologies and diseases. The tight regulation of these immune sensors is necessary to control an optimal inflammatory response and recover organism homeostasis. Prolonged activation of inflammasomes result in the development [...] Read more.
Inflammasomes are immune cytosolic oligomers involved in the initiation and progression of multiple pathologies and diseases. The tight regulation of these immune sensors is necessary to control an optimal inflammatory response and recover organism homeostasis. Prolonged activation of inflammasomes result in the development of chronic inflammatory diseases, and the use of small drug-like inhibitory molecules are emerging as promising anti-inflammatory therapies. Different aspects have to be taken in consideration when designing inflammasome inhibitors. This review summarizes the different techniques that can be used to study the mechanism of action of potential inflammasome inhibitory molecules. Full article
(This article belongs to the Special Issue Inflammasome Inhibitors)
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19 pages, 1286 KiB  
Review
NLRP3 Inflammasome Inhibitors in Cardiovascular Diseases
by Eleonora Mezzaroma, Antonio Abbate and Stefano Toldo
Molecules 2021, 26(4), 976; https://doi.org/10.3390/molecules26040976 - 12 Feb 2021
Cited by 44 | Viewed by 5864
Abstract
Virtually all types of cardiovascular diseases are associated with pathological activation of the innate immune system. The NACHT, leucine-rich repeat (LRR), and pyrin domain (PYD)-containing protein 3 (NLRP3) inflammasome is a protein complex that functions as a platform for rapid induction of the [...] Read more.
Virtually all types of cardiovascular diseases are associated with pathological activation of the innate immune system. The NACHT, leucine-rich repeat (LRR), and pyrin domain (PYD)-containing protein 3 (NLRP3) inflammasome is a protein complex that functions as a platform for rapid induction of the inflammatory response to infection or sterile injury. NLRP3 is an intracellular sensor that is sensitive to danger signals, such as ischemia and extracellular or intracellular alarmins during tissue injury. The NLRP3 inflammasome is regulated by the presence of damage-associated molecular patterns and initiates or amplifies inflammatory response through the production of interleukin-1β (IL-1β) and/or IL-18. NLRP3 activation regulates cell survival through the activity of caspase-1 and gasdermin-D. The development of NLRP3 inflammasome inhibitors has opened the possibility to targeting the deleterious effects of NLRP3. Here, we examine the scientific evidence supporting a role for NLRP3 and the effects of inhibitors in cardiovascular diseases. Full article
(This article belongs to the Special Issue Inflammasome Inhibitors)
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12 pages, 515 KiB  
Review
The Role of the Inflammasome in Neurodegenerative Diseases
by Federica Piancone, Francesca La Rosa, Ivana Marventano, Marina Saresella and Mario Clerici
Molecules 2021, 26(4), 953; https://doi.org/10.3390/molecules26040953 - 11 Feb 2021
Cited by 80 | Viewed by 6382
Abstract
Neurodegenerative diseases are chronic, progressive disorders that occur in the central nervous system (CNS). They are characterized by the loss of neuronal structure and function and are associated with inflammation. Inflammation of the CNS is called neuroinflammation, which has been implicated in most [...] Read more.
Neurodegenerative diseases are chronic, progressive disorders that occur in the central nervous system (CNS). They are characterized by the loss of neuronal structure and function and are associated with inflammation. Inflammation of the CNS is called neuroinflammation, which has been implicated in most neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). Much evidence indicates that these different conditions share a common inflammatory mechanism: the activation of the inflammasome complex in peripheral monocytes and in microglia, with the consequent production of high quantities of the pro-inflammatory cytokines IL-1β and IL-18. Inflammasomes are a group of multimeric signaling complexes that include a sensor Nod-like receptor (NLR) molecule, the adaptor protein ASC, and caspase-1. The NLRP3 inflammasome is currently the best-characterized inflammasome. Multiple signals, which are potentially provided in combination and include endogenous danger signals and pathogens, trigger the formation of an active inflammasome, which, in turn, will stimulate the cleavage and the release of bioactive cytokines including IL-1β and IL-18. In this review, we will summarize results implicating the inflammasome as a pivotal player in the pathogenesis of neurodegenerative diseases and discuss how compounds that hamper the activation of the NLRP3 inflammasome could offer novel therapeutic avenues for these diseases. Full article
(This article belongs to the Special Issue Inflammasome Inhibitors)
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20 pages, 792 KiB  
Review
Inflammasomes and the Maintenance of Hematopoietic Homeostasis: New Perspectives and Opportunities
by Lijing Yang, Mengjia Hu, Yukai Lu, Songling Han and Junping Wang
Molecules 2021, 26(2), 309; https://doi.org/10.3390/molecules26020309 - 9 Jan 2021
Cited by 15 | Viewed by 3441
Abstract
Hematopoietic stem cells (HSCs) regularly produce various blood cells throughout life via their self-renewal, proliferation, and differentiation abilities. Most HSCs remain quiescent in the bone marrow (BM) and respond in a timely manner to either physiological or pathological cues, but the underlying mechanisms [...] Read more.
Hematopoietic stem cells (HSCs) regularly produce various blood cells throughout life via their self-renewal, proliferation, and differentiation abilities. Most HSCs remain quiescent in the bone marrow (BM) and respond in a timely manner to either physiological or pathological cues, but the underlying mechanisms remain to be further elucidated. In the past few years, accumulating evidence has highlighted an intermediate role of inflammasome activation in hematopoietic maintenance, post-hematopoietic transplantation complications, and senescence. As a cytosolic protein complex, the inflammasome participates in immune responses by generating a caspase cascade and inducing cytokine secretion. This process is generally triggered by signals from purinergic receptors that integrate extracellular stimuli such as the metabolic factor ATP via P2 receptors. Furthermore, targeted modulation/inhibition of specific inflammasomes may help to maintain/restore adequate hematopoietic homeostasis. In this review, we will first summarize the possible relationships between inflammasome activation and homeostasis based on certain interesting phenomena. The cellular and molecular mechanism by which purinergic receptors integrate extracellular cues to activate inflammasomes inside HSCs will then be described. We will also discuss the therapeutic potential of targeting inflammasomes and their components in some diseases through pharmacological or genetic strategies. Full article
(This article belongs to the Special Issue Inflammasome Inhibitors)
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14 pages, 4140 KiB  
Review
Inhibiting the NLRP3 Inflammasome
by Lina Y. El-Sharkawy, David Brough and Sally Freeman
Molecules 2020, 25(23), 5533; https://doi.org/10.3390/molecules25235533 - 25 Nov 2020
Cited by 76 | Viewed by 11699
Abstract
Inflammasomes are protein complexes which are important in several inflammatory diseases. Inflammasomes form part of the innate immune system that triggers the activation of inflammatory cytokines interleukin (IL)-1β and IL-18. The inflammasome most studied in sterile inflammation and non-communicable disease is the NLRP3 [...] Read more.
Inflammasomes are protein complexes which are important in several inflammatory diseases. Inflammasomes form part of the innate immune system that triggers the activation of inflammatory cytokines interleukin (IL)-1β and IL-18. The inflammasome most studied in sterile inflammation and non-communicable disease is the NLRP3 inflammasome. Upon activation by diverse pathogen or disease associated signals, NLRP3 nucleates the oligomerization of an adaptor protein ASC forming a platform (the inflammasome) for the recruitment and activation of the protease caspase-1. Active caspase-1 catalyzes the processing and release of IL-1β and IL-18, and via cleavage of the pore forming protein gasdermin D can drive pyroptotic cell death. This review focuses on the structural basis and mechanism for NLRP3 inflammasome signaling in the context of drug design, providing chemical structures, activities, and clinical potential of direct inflammasome inhibitors. A cryo-EM structure of NLRP3 bound to NEK7 protein provides structural insight and aids in the discovery of novel NLRP3 inhibitors utilizing ligand-based or structure-based approaches. Full article
(This article belongs to the Special Issue Inflammasome Inhibitors)
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42 pages, 3820 KiB  
Review
ATP-Binding and Hydrolysis in Inflammasome Activation
by Christina F. Sandall, Bjoern K. Ziehr and Justin A. MacDonald
Molecules 2020, 25(19), 4572; https://doi.org/10.3390/molecules25194572 - 7 Oct 2020
Cited by 46 | Viewed by 6792
Abstract
The prototypical model for NOD-like receptor (NLR) inflammasome assembly includes nucleotide-dependent activation of the NLR downstream of pathogen- or danger-associated molecular pattern (PAMP or DAMP) recognition, followed by nucleation of hetero-oligomeric platforms that lie upstream of inflammatory responses associated with innate immunity. As [...] Read more.
The prototypical model for NOD-like receptor (NLR) inflammasome assembly includes nucleotide-dependent activation of the NLR downstream of pathogen- or danger-associated molecular pattern (PAMP or DAMP) recognition, followed by nucleation of hetero-oligomeric platforms that lie upstream of inflammatory responses associated with innate immunity. As members of the STAND ATPases, the NLRs are generally thought to share a similar model of ATP-dependent activation and effect. However, recent observations have challenged this paradigm to reveal novel and complex biochemical processes to discern NLRs from other STAND proteins. In this review, we highlight past findings that identify the regulatory importance of conserved ATP-binding and hydrolysis motifs within the nucleotide-binding NACHT domain of NLRs and explore recent breakthroughs that generate connections between NLR protein structure and function. Indeed, newly deposited NLR structures for NLRC4 and NLRP3 have provided unique perspectives on the ATP-dependency of inflammasome activation. Novel molecular dynamic simulations of NLRP3 examined the active site of ADP- and ATP-bound models. The findings support distinctions in nucleotide-binding domain topology with occupancy of ATP or ADP that are in turn disseminated on to the global protein structure. Ultimately, studies continue to reveal how the ATP-binding and hydrolysis properties of NACHT domains in different NLRs integrate with signaling modules and binding partners to control innate immune responses at the molecular level. Full article
(This article belongs to the Special Issue Inflammasome Inhibitors)
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25 pages, 1889 KiB  
Review
Does NLRP3 Inflammasome and Aryl Hydrocarbon Receptor Play an Interlinked Role in Bowel Inflammation and Colitis-Associated Colorectal Cancer?
by Ivan Qi Han Ngui, Agampodi Promoda Perera and Rajaraman Eri
Molecules 2020, 25(10), 2427; https://doi.org/10.3390/molecules25102427 - 22 May 2020
Cited by 28 | Viewed by 5621
Abstract
Inflammation is a hallmark in many forms of cancer; with colitis-associated colorectal cancer (CAC) being a progressive intestinal inflammation due to inflammatory bowel disease (IBD). While this is an exemplification of the negatives of inflammation, it is just as crucial to have some [...] Read more.
Inflammation is a hallmark in many forms of cancer; with colitis-associated colorectal cancer (CAC) being a progressive intestinal inflammation due to inflammatory bowel disease (IBD). While this is an exemplification of the negatives of inflammation, it is just as crucial to have some degree of the inflammatory process to maintain a healthy immune system. A pivotal component in the maintenance of such intestinal homeostasis is the innate immunity component, inflammasomes. Inflammasomes are large, cytosolic protein complexes formed following stimulation of microbial and stress signals that lead to the expression of pro-inflammatory cytokines. The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome has been extensively studied in part due to its strong association with colitis and CAC. The aryl hydrocarbon receptor (AhR) has recently been acknowledged for its connection to the immune system aside from its role as an environmental sensor. AhR has been described to play a role in the inhibition of the NLRP3 inflammasome activation pathway. This review will summarise the signalling pathways of both the NLRP3 inflammasome and AhR; as well as new-found links between these two signalling pathways in intestinal immunity and some potential therapeutic agents that have been found to take advantage of this link in the treatment of colitis and CAC. Full article
(This article belongs to the Special Issue Inflammasome Inhibitors)
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