Inflammasomes in Intestinal Disease: Mechanisms of Activation and Therapeutic Strategies
Abstract
1. Introduction
2. Inflammasome Sensors
2.1. NLRP1
2.2. NLRP3
2.3. NLRC4
2.4. NLRP6
2.5. AIM2-like Receptors
2.6. Pyrin Inflammasome
3. Role of Inflammasomes in Intestinal Diseases
3.1. Irritable Bowel Disease
3.2. Celiac Disease
3.3. Inflammatory Bowel Disease
3.4. Colorectal Cancer
4. Strategies to Inhibit the Inflammasomes Pathways
4.1. Pharmaceutical Inhibitors
4.2. Natural Compounds
4.3. microRNA
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Phase | Inhibitor | Target | Mechanism of Action | Experimental Models | References |
---|---|---|---|---|---|
Inflammasome Sensors | MCC950 | NLRP3 | Blocks canonical and non-canonical inflammasome activation binding NACHT domain and reduces IL-1β secretion | Spontaneous colitis mice | [101,102,103,104] |
DSS-induced colitis using Nod2 knockout mice | |||||
DSS-induced colitis mice | |||||
OLT117 | NLRP3 | Inhibits canonical and non-canonical inflammasome activation binding NACHT domain | DSS-induced colitis mice | [105] | |
Tranilast | NLRP3 | Influences the activation of inflammasome by binding NACHT domain Inhibits visceral hypersensitivity and colon permeability | DSS-induced colitis mice | [106,107,108,109] | |
DSS-induced colitis rats | |||||
Mouse BMDMs and THP1 | |||||
IBS rat models | |||||
G514-0208 | NLRP3 | Selectively inhibitor via NACHT domain binding | DSS-induced colitis mice | [110] | |
NF-κB Pathway | MCC950 | NF-κB | In combination with metformin, inhibits the priming and activation of inflammasomes via TLR4/NF-κB and induces autophagy | DSS-induced colitis rats | [111] |
Dapagliflozin | NLRP3 | Inhibits inflammasome activation via the NF-κB/AMPK/NLRP3 axis | Acetic acid-induced colitis in rats | [112] | |
Canagliflozin | NLRP3 | Inhibits inflammasome activation via the NF-κB/AMPK/NLRP3 axis | Acetic acid-induced colitis in rats. | [113] | |
Oridonin | NF-κB | Inhibits inflammasome activation via NF-κB and reduced cytokines expression | TNBS-induced colitis mice | [114] | |
Mirtazapine | NLRP3 | Blocks inflammasome activation, modulating NF-κB activation and the NLRP3/caspase-1 signaling pathway | Acetic acid-induced colitis in rats | [115] | |
BAY 11-7082 | NLRP3 | Inhibits inflammasome activation by suppressing both the NF-κB and NLRP3 pathways | Mouse BMDMs | [66,116] | |
IBS rat models | |||||
Artemisinin | NLRP3 | Blocks NLRP3 inflammasome assembly by inhibiting ROS production and NF-κB and MAPK signaling | Mouse BMDMs | [117] | |
DSS-induced colitis mice | |||||
Inflammasome Activation | Glyburide | K+ efflux | Prevents inflammasome activation through the inhibition of K+ efflux | Mouse BMDMs | [77,118] |
IL10−/− mouse model | |||||
BHB | K+ efflux | Prevents inflammasome activation through the inhibition of K+ efflux and ASC oligomerization Reduces cytokine inflammasome-related release and mitigates pyroptosis | Mouse BMDMs | [119,120] | |
DSS-induced colitis rats | |||||
(R,R)-BD-AcAc2 | NLRP3 | Prevents inflammasome activation and pyroptosis | DSS-induced colitis rats | [121] | |
RRx-001 | NEK7 | Covalent binding to the cysteine residue, preventing NLRP3-NEK7 interaction; attenuates experimental colitis | Mouse BMDMs; | [122] | |
DSS-induced colitis mice | |||||
WT161 | NLRP3 | Inhibits NLRP3 activation by blocking HDAC6 | DSS-induced colitis mice | [123] | |
Mouse BMDMs | |||||
C646 | NLRP3 | Inhibits NLRP3 activation by blocking histone acetyltransferase p300 | DSS-induced colitis mice | [124] | |
Mouse BMDMs | |||||
Metformin | NLRP3 | Suppresses inflammatory processes and regulates the inflammatory microenvironment | LS1034 | [125] | |
BayK8644 | TMEM176B | Triggers NLRP3 inflammasomes activation and limits the tumor growth | CRC mouse model | [126] | |
THP-1 | |||||
Mouse BMDMs | |||||
Caspase-1 Activation and Pyroptosis | Artemisinin | NLRC4 AIM2 | Inhibits Il-1β secretion | Mouse BMDMs | [117] |
DSS-induced colitis mice | |||||
Pralnacasan | Caspase-1 | Inhibits caspase-1 activation | DSS-induced colitis mice | [30] | |
Mouse BMDMs | |||||
THP-1 | |||||
Ac-YVAD-cmk | Caspase-1 | Inhibits caspase-1 activation | DSS-induced colitis mice | [127] | |
Mouse BMDMs | |||||
Santacrumazate A | NLRP3 | Inhibits HDAC2 expression and, in combination with antitumor agents, activates NLRP3/GSDMD-mediated pyroptosis | SW620 | [128] | |
LS174T | |||||
Lobaplatin | GSDME | Induces pyroptosis via GSDME activation | HT29 | [129] | |
HCT116 | |||||
Simvastatin | NLRP3 | Induces intracellular ROS production and triggers the NLRP3/caspase-1 pathway and pyroptosis | HCT116 | [130] | |
SW620 | |||||
FL118 | NLRP3 | Induces NLRP3-ASC-caspase-1 mediated pyroptosis | SW480 | [131] | |
HT29 | |||||
A438079 | P2X7 | Induces Bcl2/caspase-9/caspase-3 apoptosis and NLRP3/caspase-1 pyroptosis | HCT116 | [132] | |
SW620 |
Phase | Natural Compounds | Target | Mechanism of Action | Experimental Models | References |
---|---|---|---|---|---|
NF-κB Pathway | Naringin | NF-κB | Suppresses the activation of NF-κB, preventing the NLRP3 inflammasome signaling pathway | DSS-induced colitis mice | [140] |
Procyanidin | NF-κB | Suppresses the activation of NF-κB, preventing NLRP3 inflammasome activation | DSS-induced colitis mice | [141] | |
THP-1 | |||||
Phloretin | NF-κB | Suppresses the activation of NF-κB, preventing NLRP3 inflammasome activation | DSS-induced colitis mice | [142] | |
Formononetin | NLRP3 | Inhibits the NLRP3 signaling pathway | DSS-induced colitis mice | [143] | |
Genistein | NLRP3 | Inhibits the NLRP3 signaling pathway | DSS-induced colitis mice | [144] | |
THP-1 | |||||
Celastrol | NF-κB | Inhibits NLRP3 inflammasome activation and contrasts oxidative stress | DSS-induced colitis mice | [145] | |
Evodiamine | NF-κB | Modulates NLRP3 inflammasome activation | DSS-induced colitis mice | [146] | |
Bergenin | NF-κB | Blocks the canonical and non-canonical NLRP3 inflammasome pathways | DSS-induced colitis rats | [147] | |
Secoisolariciresinol diglucoside | NF-κB | Inhibits NLRP1 inflammasome activation | DSS-induced colitis mice Raw264.7 | [148] | |
Inflammasome Activation | Cardamonin | Nrf2 | Inhibits NLRP3 inflammasome activation by inducing activation of the AhR/Nrf2/NQO1 pathway | DSS-induced colitis mice | [149] |
TNBS-induced colitis mice | |||||
BMDMs | |||||
THP-1 | |||||
Dimethyl fumarate | Nrf2 | Reduces NLRP3 inflammasome activation by inducing Nrf2 pathway activation | DSS-induced colitis mice | [150] | |
THP-1 | |||||
Coptisine | Nrf2 | Modulates the expression levels of NLRP3 inflammasome components, increasing the expression of Nrf2 | PI-IBS rats | [151] | |
Luteolin | ROS | Inhibits NLRP3 inflammasomes activation and promotes macrophage polarization | Raw264.7 | [152] | |
Atractylenolide | DRP1 | Inhibits NLRP3 inflammasome activation via mitochondrial damage suppression | AOM/DSS mice | [153] | |
Parthenolide | NEK7 K+ efflux | Inhibits NLRP3 inflammasome assembly, affecting NLRP3/NEK7 interaction Inhibits NLRP3 inflammasome activation by suppressing K+ efflux | Murine BMDMs | [116,154] | |
THP-1 | |||||
Curcumin | K+ efflux | Inhibits activation of the NLRP3 inflammasome, reducing ROS and Cathepsin B release | DSS-induced colitis mice | [155] | |
Vitamine D3 | NEK7 | Impairs NLRP3/NEK7 interaction, suppressing NLRP3 inflammasome assembly and activation | DSS-induced colitis mice | [156] | |
Ginsenosides | NLRP3 | Reduces NLRP3 inflammasome activation | DSS-induced colitis mice | [157,158] | |
Salidroside | NLRP3 | Modulates NLRP3 inflammasome activation and downstream pro-inflammatory mediators | DSS-induced colitis mice | [159] | |
Palmatine | NLRP3 | Modulates NLRP3 inflammasome activation and increases mitophagy | DSS-induced colitis mice | [160] | |
Cinnamadehyde | NLRP3 | Inhibits activation of the NLRP3 inflammasome and restores the NLRP3-related inflammatory mediators | DSS-induced colitis mice | [161,162] | |
Paeoniflorin | miR-29a | Modulates NLRP3 inflammasome activation | IBS mice | [163] | |
CJAF | NLRP3 | Modulates NLRP3 inflammasome activation and downstream pro-inflammatory mediators | IBS mice | [164] | |
Eugeniin | NLRC4 | Reduces NAIP/NLRC4 inflammasome activation by bacterial pathogenic components | DSS-induced colitis mice | [38] | |
Raw264.7 | |||||
THP-1 | |||||
Arctigenin | NLRP3 | Inhibits NLRP3 inflammasome assembly and activation | AOM/DSS mice | [165] | |
Andrographolide | NLRP3 | Inhibits NLRP3 inflammasome activation In combination with antitumor agents, enhances the effects of cancer therapies | DSS-induced colitis mice | [166,167] | |
AOM/DSS mice | |||||
Murine BMDMs | |||||
GL-V9 | NLRP3 | Triggers autophagy, inducing NLRP3 inflammasome degradation | DSS-induced colitis mice | [168] | |
AOM/DSS mice | |||||
THP-1 | |||||
Murine BMDMs | |||||
Caspase-1 Activation and Pyroptosis | Luteolin | Caspase-1 GSDMD IL-1β | Inhibits cell proliferation and induces pyroptosis | HT29 | [169] |
Curcumin | NLRP3 | Promotes NLRP3-mediated pyroptosis | SW480 | [170] | |
HCT116 | |||||
LoVo | |||||
HT29 | |||||
Sulforaphane | Caspase-1 | Inhibits caspase-1 cleavage and IL-1β maturation Reduces ROS levels | Raw264.7 | [171,172] | |
Murine BMDMs | |||||
DSS-induced colitis mice | |||||
VI-16 | IL-1β | Inhibits NLRP3 inflammasome activation and IL-1β release | DSS-induced colitis mice | [173] | |
THP-1 | |||||
Post-Transcriptional Modification | CAPE | NLRP3 | Promotes NLRP3 ubiquitination and degradation | AOM/DSS mice | [165] |
Phase | miRNAs | Target | Mechanism of Action | Experimental Models | References |
---|---|---|---|---|---|
Inflammasome Activation | miR-223 | NLRP3 | Suppresses NLRP3 expression and activation | DSS-induced colitis mice | [178] |
Murine BMDMs | |||||
THP-1 | |||||
miR-21 miR-155 | NLRP3 | Cinnamadehyde inhibits activation of the NLRP3 inflammasome by reducing the expression levels of miR-21 and miR-155 | DSS-induced colitis mice | [161] | |
miR-29a | NLRP3 | Peoniflorin modulates NLRP3 inflammasome signaling by inhibiting miR-29a | IBS mice | [163] | |
miR-133a-1 | UCP2 | Reduces the expression of NLRP3 inflammasome components and downstream cytokines | THP-1 | [179] | |
miR-200c-5p | NEK7 | Reduces NLRP3 inflammasome activation and pyroptosis | DSS-induced colitis mice | [180] | |
miR-22 | NLRP3 | Reduces NLRP3 inflammasome expression, cell proliferation, migration, and invasion | HCT116 | [181] | |
mouse xenograft model | |||||
Pyroptosis | miR-223 | NLRP3 | Reduces IL-1β production and inhibits pyroptosis | DSS-induced colitis mice | [182,183] |
Murine BMDMs | |||||
THP-1 | |||||
miR-378a-5p | NLRP3 | Inhibits NLRP3 activation and pyroptosis | DSS-induced colitis mice | [184] | |
Murine BMDMs | |||||
THP-1 | |||||
Post-Transcriptional Modification | miR-369-3p | BRCC3 | Inhibits deubiquitination of NLRP3, modulating inflammasome assembly and activation | Murine BMDMs | [26] |
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Scalavino, V.; Piccinno, E.; Giannelli, G.; Serino, G. Inflammasomes in Intestinal Disease: Mechanisms of Activation and Therapeutic Strategies. Int. J. Mol. Sci. 2024, 25, 13058. https://doi.org/10.3390/ijms252313058
Scalavino V, Piccinno E, Giannelli G, Serino G. Inflammasomes in Intestinal Disease: Mechanisms of Activation and Therapeutic Strategies. International Journal of Molecular Sciences. 2024; 25(23):13058. https://doi.org/10.3390/ijms252313058
Chicago/Turabian StyleScalavino, Viviana, Emanuele Piccinno, Gianluigi Giannelli, and Grazia Serino. 2024. "Inflammasomes in Intestinal Disease: Mechanisms of Activation and Therapeutic Strategies" International Journal of Molecular Sciences 25, no. 23: 13058. https://doi.org/10.3390/ijms252313058
APA StyleScalavino, V., Piccinno, E., Giannelli, G., & Serino, G. (2024). Inflammasomes in Intestinal Disease: Mechanisms of Activation and Therapeutic Strategies. International Journal of Molecular Sciences, 25(23), 13058. https://doi.org/10.3390/ijms252313058