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Inflammasomes as the Target of Pharmacotherapy

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Biopharmaceuticals".

Deadline for manuscript submissions: closed (20 December 2023) | Viewed by 13526

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Special Issue Editors

Dr. Francesca La Rosa

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Guest Editor

IRCCS Fondazione Don C. Gnocchi, ONLUS, 20148 Milan, Italy
Interests: neurodegenerative diseases; Alzheimer’s disease; dementia; cell biology; molecular biology; ageing; therapeutics and rehabilitation

Dr. Marina Saresella

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Guest Editor

IRCCS Fondazione Don C. Gnocchi, ONLUS, 20148 Milan, Italy
Interests: neuroinflammation; cytokines; inflammasome; lymphocyte immunophenotype; multiple sclerosis; Alzheimer's disease; neurodevelopment disorders

Special Issue Information

Dear Colleagues,

As a sensor of infections and external stimuli, inflammasomes play a key role in the pathological process of various diseases [1]. Inflammasomes are intracellular multimeric complex molecules [1] including: i) canonical inflammasomes (NLRP3, NLRC4, and AIM2) that serve as a platform to engage pro-caspase-1, which becomes active caspase-1 and processes pro-interleukin-1β (IL-1β) and pro-IL-18 to generate their active forms, inducing pyroptosis, a pro-inflammatory form of cell death [2,3–5]; and ii) noncanonical inflammasomes that activate caspase-11 (mouse) or caspase-4/5 (human) without cleaving pro-IL-1β [1,6].

Available compounds act mainly by inhibiting the products of inflammasome activation, for example, by impeding the biological effects of downstream interleukins [7,8], but given the lack of effective drugs in the therapy of different inflammatory chronic conditions, it is becoming particularly pressing to understand and provide a potentially practical pharmacological approach for treating NLRP3-driven diseases.

In this Special Issue, we aim to gather research from experts in the field that highlights therapeutic agents and strategies to identify future discoveries and therapies for “inflammasomes”-mediated inflammatory disorders.

[1] Lamkanfi, M. & Dixit, V. M. Mechanisms and functions of inflammasomes. Cell 157, 1013–1022 (2014).

[2] Martinon, F., Burns, K. & Tschopp, J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol. Cell 10, 417–426 (2002).

[3] Dinarello, C. A. Immunological and inflammatory functions of the interleukin-1 family. Annu. Rev. Immunol. 27, 519–550 (2009).

[4] Rathinam, V. A., Vanaja, S. K. & Fitzgerald, K. A. Regulation of inflammasome signaling. Nat. Immunol. 13, 333–342 (2012).

[5] Thornberry, N. A. et al. A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes. Nature 356, 768–774 (1992).

[6] Hagar, J. A., Powell, D. A., Aachoui, Y., Ernst, R. K. & Miao, E. A. Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock. Science 341, 1250–1253 (2013).

[7] La Rosa F, Saresella M, Marventano I, Piancone F, Ripamonti E, Al-Daghri N, Bazzini C, Zoia CP, Conti E, Ferrarese C, et al. Stavudine Reduces NLRP3 Inflammasome Activation and Modulates Amyloid-β Autophagy. J. Alzheimers Dis. 72, 401-412 (2019).

[8] La Rosa F, Mancuso R, Agostini S, Piancone F, Marventano I, Saresella M, Hernis A, Fenoglio C, Galimberti D, Scarpini E, Clerici M. Pharmacological and Epigenetic Regulators of NLRP3 Inflammasome Activation in Alzheimer's Disease. Pharmaceuticals 14, 1187 (2021).

Dr. Francesca La Rosa
Dr. Marina Saresella
Guest Editors

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Keywords

cytokines
inflammasome
inflammation
interleukin
molecule inhibitor
rehabilitation
targeted therapy

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Published Papers (7 papers)

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20 pages, 3753 KiB

Open AccessArticle

Implications of NLRP3 Suppression Using Glibenclamide and miR-223 against Colorectal Cancer

by Shaimaa Hamza, Ekaterina E. Garanina, Layaly Shkair, Mohammad Alsaadi, Svetlana F. Khaiboullina and Gulcin Tezcan

Pharmaceuticals 2024, 17(3), 299; https://doi.org/10.3390/ph17030299 - 26 Feb 2024

Cited by 1 | Viewed by 1707

Abstract

The NLR family pyrin domain containing 3 (NLRP3) promotes the growth of colorectal cancer (CRC). However, the therapeutic effect of NLRP3 inhibition on CRC cell progression is controversial. This study comparatively investigated the therapeutic effect of a pharmacological NLRP3 inhibitor, glibenclamide (gli), and the post-translational suppression of NLRP3 by miR-223 on CRC cell progression in HCT-116 and HCT-15 cells. LPS and ATP were used to activate Gli-treated and LSB-hsa-miR-223-3p (WT^miR-223)-expressing HCT-116 cells. NLRP3.AB.pCCL.sin.cPPT.U6.miR-223-Decoy.hPGK.GFP.WPRE plasmid (D^miR-223) was the negative control for miR-223 expression. NLRP3, gasdermin D, and BAX expressions were analyzed using western blotting. Real-time PCR detected the RNA expression of autophagy-related genes ATG5, BECN1, and miR-223 in non-transfected cells. ELISA analyzed IL-1β and IL-18 in the medium. MTS-1, annexin V, wound-healing, and sphere-invasion assays were used to assess cell viability and progression. A multiplex cytokine assay detected proinflammatory cytokine secretion. LPS–ATP-activated NLRP3 produced gasdermin D cleavage, released IL-1b and IL-18, and activated cell migration and sphere invasion. In contrast, reduced cell growth, miR-223 expression, IFN-γ, CXCL10, and LIF secretion were found in cells after inflammasome activation. Both gli and WT^miR-223 induced autophagy genes ATG5 and BECN1 and reduced the NLRP3 activation and its downstream proteins. However, while gli had a limited effect on the production of IFN-γ, CXCL10, and LIF, WTmiR-223 increased the release of those cytokines. In addition, gli did not suppress cell growth, while WTmiR-223 promoted apoptosis. Notably, neither gli nor WTmiR-223 effectively prevented sphere invasion. These data suggest that, while WT^miR-223 could have a better anticancer effect in CRC compared to gli, the sole usage of miR-223-mediated NLRP3 suppression may not be sufficient to prevent CRC metastasis. Full article

(This article belongs to the Special Issue Inflammasomes as the Target of Pharmacotherapy)

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13 pages, 2302 KiB

Open AccessArticle

Glibenclamide-Loaded Nanoparticles Reduce NLRP3 Inflammasome Activation and Modulate miR-223-3p/miR-7-1-5p Expression in THP-1 Cells

by Roberta Mancuso, Lorenzo Agostino Citterio, Simone Agostini, Ivana Marventano, Francesca La Rosa, Francesca Re, Pierfausto Seneci, Marina Saresella and Mario Clerici

Pharmaceuticals 2023, 16(11), 1590; https://doi.org/10.3390/ph16111590 - 10 Nov 2023

Cited by 2 | Viewed by 1506

Abstract

The anti-hyperglycemic drug glibenclamide (Glb) might represent an interesting therapeutic option in human neurodegenerative diseases because of its anti-inflammatory activity and its ability to downregulate activation of the NLRP3 inflammasome. Bi-functionalized liposomes that can cross the blood–brain barrier (BBB) may be used to release Glb into the central nervous system (CNS), overcoming its poor solubility and bioavailability. Here, we analyzed in vitro the effect of Glb-loaded nanovectors (GNVs) and Glb itself on NLRP3 inflammasome activation using a lipopolysaccharide- and nigericine-activated THP-1 cell model. Apoptosis-associated speck-like protein containing a CARD (ASC) aggregation and NLRP3-related cytokine (IL-1β, caspase 1, and IL-18) production and gene expression, as well as the concentration of miR-223-3p and miR-7-1-5p, known to modulate the NLRP3 inflammasome, were evaluated in all conditions. Results showed that both GNVs and Glb reduced significantly ASC-speck oligomerization, transcription and translation of NLRP3, as well as the secretion of caspase 1 and IL-1β (p < 0.05 for all). Unexpectedly, GNVs/Glb significantly suppressed miR-223-3p and upregulated miR-7-1-5p expression (p < 0.01). These preliminary results thus suggest that GNVs, similarly to Glb, are able to dampen NLRP3 inflammasome activation, inflammatory cytokine release, and modulate miR-223-3p/miR-7-1-5p. Although the mechanisms underlying the complex relation among these elements remain to be further investigated, these results can open new roads to the use of GNVs as a novel strategy to reduce inflammasome activation in disease and rehabilitation. Full article

(This article belongs to the Special Issue Inflammasomes as the Target of Pharmacotherapy)

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16 pages, 2816 KiB

Open AccessArticle

Neural–Cardiac Inflammasome Axis after Traumatic Brain Injury

by Robert W. Keane, Roey Hadad, Xavier O. Scott, Erika d. l. R. M. Cabrera Ranaldi, Jon Pérez-Bárcena and Juan Pablo de Rivero Vaccari

Pharmaceuticals 2023, 16(10), 1382; https://doi.org/10.3390/ph16101382 - 28 Sep 2023

Cited by 6 | Viewed by 1626

Abstract

Traumatic brain injury (TBI) affects not only the brain but also peripheral organs like the heart and the lungs, which influences long-term outcomes. A heightened systemic inflammatory response is often induced after TBI, but the underlying pathomechanisms that contribute to co-morbidities remain poorly understood. Here, we investigated whether extracellular vehicles (EVs) containing inflammasome proteins are released after severe controlled cortical impact (CCI) in C57BL/6 mice and cause activation of inflammasomes in the heart that result in tissue damage. The atrium of injured mice at 3 days after TBI showed a significant increase in the levels of the inflammasome proteins AIM2, ASC, caspases-1, -8 and -11, whereas IL-1β was increased in the ventricles. Additionally, the injured cortex showed a significant increase in IL-1β, ASC, caspases-1, -8 and -11 and pyrin at 3 days after injury when compared to the sham. Serum-derived extracellular vesicles (EVs) from injured patients were characterized with nanoparticle tracking analysis and Ella Simple Plex and showed elevated levels of the inflammasome proteins caspase-1, ASC and IL-18. Mass spectrometry of serum-derived EVs from mice after TBI revealed a variety of complement- and cardiovascular-related signaling proteins. Moreover, adoptive transfer of serum-derived EVs from TBI patients resulted in inflammasome activation in cardiac cells in culture. Thus, TBI elicits inflammasome activation, primarily in the atrium, that is mediated, in part, by EVs that contain inflammasome- and complement-related signaling proteins that are released into serum and contribute to peripheral organ systemic inflammation, which increases inflammasome activation in the heart. Full article

(This article belongs to the Special Issue Inflammasomes as the Target of Pharmacotherapy)

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14 pages, 4844 KiB

Open AccessArticle

Quercetin Alleviated Inflammasome-Mediated Pyroptosis and Modulated the mTOR/P70S6/P6/eIF4E/4EBP1 Pathway in Ischemic Stroke

by Abdullah Alattar, Reem Alshaman, Yusuf S. Althobaiti, Ghareb M. Soliman, Howaida S. Ali, Waleed Salman Khubrni, Phil Ok Koh, Najeeb Ur Rehman and Fawad Ali Shah

Pharmaceuticals 2023, 16(8), 1182; https://doi.org/10.3390/ph16081182 - 21 Aug 2023

Cited by 5 | Viewed by 2026

Abstract

Stroke ranks as the world’s second most prevalent cause of mortality, and it represents a major public health concern with profound economic and social implications. In the present study, we elucidated the neuroprotective role of quercetin on NLRP3-associated pyroptosis, Nrf2-coupled anti-inflammatory, and mTOR-dependent downstream pathways. Male Sprague Dawley rats were subjected to 72 h of transient middle cerebral artery ischemia, followed by the administration of 10 mg/kg of quercetin. Our findings demonstrated that MCAO induced elevated ROS which were coupled to inflammasome-mediated pyroptosis and altered mTOR-related signaling proteins. We performed ELISA, immunohistochemistry, and Western blotting to unveil the underlying role of the Nrf2/HO-1 and PDK/AKT/mTOR pathways in the ischemic cortex and striatum. Our results showed that quercetin post-treatment activated the Nrf2/HO-1 cascade, reversed pyroptosis, and modulated the autophagy-related pathway PDK/AKT/mTOR/P70S6/P6/eIF4E/4EBP1. Further, quercetin enhances the sequestering effect of 14-3-3 and reversed the decrease in interaction between p-Bad and 14-3-3 and p-FKHR and 14-3-3. Our findings showed that quercetin exerts its protective benefits and rescues neuronal damage by several mechanisms, and it might be a viable neuroprotective drug for ischemic stroke therapy. Full article

(This article belongs to the Special Issue Inflammasomes as the Target of Pharmacotherapy)

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13 pages, 1675 KiB

Open AccessArticle

Proof-of-Principle Study of Inflammasome Signaling Proteins as Diagnostic Biomarkers of the Inflammatory Response in Parkinson’s Disease

by Erika d. l. R. M. Cabrera Ranaldi, Karen Nuytemans, Anisley Martinez, Corneliu C. Luca, Robert W. Keane and Juan Pablo de Rivero Vaccari

Pharmaceuticals 2023, 16(6), 883; https://doi.org/10.3390/ph16060883 - 15 Jun 2023

Cited by 8 | Viewed by 1983

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder marked by the death of dopaminergic neurons in the midbrain, the accumulation of α-synuclein aggregates, and motor deficits. A major contributor to dopaminergic neuronal loss is neuroinflammation. The inflammasome is a multiprotein complex that perpetuates neuroinflammation in neurodegenerative disorders including PD. Increases in inflammasome proteins are associated with worsened pathology. Thus, the inhibition of inflammatory mediators has the potential to aid in PD treatment. Here, we investigated inflammasome signaling proteins as potential biomarkers of the inflammatory response in PD. Plasma from PD subjects and healthy age-matched controls were evaluated for levels of the inflammasome protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, and interleukin (IL)-18. This was carried out using Simple Plex technology to identify changes in inflammasome proteins in the blood of PD subjects. The area under the curve (AUC) was obtained through calculation of the receiver operating characteristics (ROC) to obtain information on biomarker reliability and traits. Additionally, we completed a stepwise regression selected from the lowest Akaike information criterion (AIC) to assess how the inflammasome proteins caspase-1 and ASC contribute to IL-18 levels in people with PD. PD subjects demonstrated elevated caspase-1, ASC, and IL-18 levels when compared to controls; each of these proteins were found to be promising biomarkers of inflammation in PD. Furthermore, inflammasome proteins were determined to significantly contribute to and predict IL-18 levels in subjects with PD. Thus, we demonstrated that inflammasome proteins serve as reliable biomarkers of inflammation in PD and that inflammasome proteins provide significant contributions to IL-18 levels in PD. Full article

(This article belongs to the Special Issue Inflammasomes as the Target of Pharmacotherapy)

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18 pages, 4160 KiB

Open AccessArticle

Targeting Spike Glycoprotein S1 Mediated by NLRP3 Inflammasome Machinery and the Cytokine Releases in A549 Lung Epithelial Cells by Nanocurcumin

by Chuda Chittasupho, Kamonwan Srisawad, Punnida Arjsri, Rungsinee Phongpradist, Wipawan Tingya, Chadarat Ampasavate and Pornngarm Dejkriengkraikul

Pharmaceuticals 2023, 16(6), 862; https://doi.org/10.3390/ph16060862 - 9 Jun 2023

Cited by 6 | Viewed by 1894

Abstract

Chronic inflammation and tissue damage can result from uncontrolled inflammation during SARS-CoV-2 or COVID-19 infections, leading to post-acute COVID conditions or long COVID. Curcumin, found in turmeric, has potent anti-inflammatory properties but limited effectiveness. This study developed nanocurcumin, a curcumin nanoparticle, to enhance its physical and chemical stability and investigate its in vitro anti-inflammatory properties upon CoV2-SP induction in lung epithelial cells. Nanocurcumin was prepared by encapsulating curcumin extract in phospholipids. The particle size, polydispersity index, and zeta potential of nanocurcumin were measured using dynamic light scattering. The encapsulated curcumin content was determined using HPLC analysis. The encapsulation efficiency of curcumin was 90.74 ± 5.35% as determined by HPLC. Regarding the in vitro release of curcumin, nanocurcumin displayed a higher release content than non-nanoparticle curcumin. Nanocurcumin was further investigated for its anti-inflammatory properties using A549 lung epithelial cell line. As determined by ELISA, nanocurcumin showed inhibitory effects on inflammatory cytokine releases in CoV2-SP-stimulated conditions, as evidenced by a significant decrease in IL-6, IL-1β and IL-18 cytokine secretions compared with the spike-stimulated control group (p < 0.05). Additionally, as determined by RT-PCR, nanocurcumin significantly inhibited the CoV2-SP-stimulated expression of inflammatory genes (IL-6, IL-1β, IL-18, and NLRP3) compared with the spike-stimulated control group (p < 0.05). Regarding the inhibition of NLRP3 inflammasome machinery proteins by Western blot, nanocurcumin decreased the expressions of inflammasome machinery proteins including NLRP3, ASC, pro-caspase-1, and the active form of caspase-1 in CoV2-SP-stimulated A549 cells compared with the spike-stimulated control group (p < 0.05). Overall, the nanoparticle formulation of curcumin improved its solubility and bioavailability, demonstrating anti-inflammatory effects in a CoV2-SP-induced scenario by inhibiting inflammatory mediators and the NLRP3 inflammasome machinery. Nanocurcumin shows promise as an anti-inflammatory product for preventing COVID-19-related airway inflammation. Full article

(This article belongs to the Special Issue Inflammasomes as the Target of Pharmacotherapy)

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Review

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14 pages, 1347 KiB

Open AccessReview

Inflammasomes in Atherosclerosis—From Pathophysiology to Treatment

by Panagiotis Theofilis, Evangelos Oikonomou, Christos Chasikidis, Konstantinos Tsioufis and Dimitris Tousoulis

Pharmaceuticals 2023, 16(9), 1211; https://doi.org/10.3390/ph16091211 - 28 Aug 2023

Cited by 6 | Viewed by 1935

Abstract

Atherosclerosis, a chronic inflammatory disease characterized by arterial plaque accumulation, remains a significant global health challenge. In recent years, inflammasomes, the intracellular multiprotein complexes crucial for initiating innate immune responses, have emerged as key players in atherosclerosis pathophysiology. This review article aims to provide a comprehensive overview of the current understanding of inflammasome activation and its impact on atherosclerosis development and progression. We explore the intricate interplay between traditional cardiovascular risk factors and inflammasome activation, leading to the perpetuation of inflammatory cascades that drive plaque formation and instability. The review focuses on the molecular mechanisms underlying inflammasome activation, including the role of pattern recognition receptors and cytokines in this process. Moreover, we discuss the contribution of inflammasomes to endothelial dysfunction, foam cell formation, and vascular inflammation. Additionally, recent advances in therapeutic strategies targeting inflammasomes are examined, including pharmacological agents and potential immunomodulatory approaches. By collating and analyzing the current evidence, this review provides valuable insights into the potential of inflammasome-targeted therapies for atherosclerosis management and treatment. Understanding the pivotal role of inflammasomes in atherosclerosis pathophysiology offers promising prospects for developing effective and personalized therapeutic interventions that can mitigate the burden of this prevalent cardiovascular disorder and improve patient outcomes. Full article

(This article belongs to the Special Issue Inflammasomes as the Target of Pharmacotherapy)

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