Cited by 838Inflammasome and immune disordersImmune Response and InflammationAutoimmune and Inflammatory Disorders Research

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NLRP3 inflammasome and its inhibitors: a review

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Shao, Bo-Zong, Xu, Zhe-Qi, Han, Bin-Ze, Su, Ding-Feng, Liu, Chong·2015·Frontiers in Pharmacology

DOI 10.3389/fphar.2015.00262PMC PMC4633676

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Abstract

Inflammasomes are newly recognized, vital players in innate immunity. The best characterized is the NLRP3 inflammasome, so-called because the NLRP3 protein in the complex belongs to the family of nucleotide-binding and oligomerization domain-like receptors (NLRs) and is also known as "pyrin domain-containing protein 3". The NLRP3 inflammasome is associated with onset and progression of various diseases, including metabolic disorders, multiple sclerosis, inflammatory bowel disease, cryopyrin-associated periodic fever syndrome, as well as other auto-immune and auto-inflammatory diseases. Several NLRP3 inflammasome inhibitors have been described, some of which show promise in the clinic. The present review will describe the structure and mechanisms of activation of the NLRP3 inflammasome, its association with various auto-immune and auto-inflammatory diseases, and the state of research into NLRP3 inflammasome inhibitors.

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Background
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BackgroundMethod
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Background
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Background
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Background
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Background
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Background
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BackgroundInfluential
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Background
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BackgroundInfluential
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Background
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Background
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Background
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Background
NLRP3 as a potentially novel biomarker for the management of osteoarthritis
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Background
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BackgroundInfluential
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Background
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Background
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Background
Mitochondria as a centrally positioned hub in the innate immune response
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“The NLRP3 inflammasome is associated with onset and progression of various diseases, including metabolic disorders, multiple sclerosis, inflammatory bowel disease, as well as other inflammatory diseases [23].”
Colchicine Improves Survival, Left Ventricular Remodeling, and Chronic Cardiac Function After Acute Myocardial Infarction
Fujisue, K., Sugamura, K., Kurokawa, H., Matsubara, J., Ishii, M., Izumiya, Y., Kaikita, K., & Sugiyama, S. (2017) · Circulation Journal · doi:10.1253/circj.cj-16-0949 · Cited by 137
NLRP3 inflammasome activation promotes inflammation-induced carcinogenesis in head and neck squamous cell carcinoma
Huang, C., Chen, L., Li, Y., Wu, L., Yu, G., Zhang, W., & Sun, Z. (2017) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-017-0589-y · Cited by 139
“inflammasome inhibitors, MCC950 blocks ASC oligomerization to inhibit canonical and non-canonical NLRP3 inflammasome activation rather than by reducing NLRP3 protein expression [35].”
Background
Inflammasome biology, molecular pathology and therapeutic implications
Awad, F., Assrawi, E., Louvrier, C., Jumeau, C., Georgin‐Lavialle, S., Grateau, G., Amselem, S., Giurgea, I., & Karabina, S. (2018) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.02.011 · Cited by 138
PM2.5 exposure aggravates oligomeric amyloid beta-induced neuronal injury and promotes NLRP3 inflammasome activation in an in vitro model of Alzheimer’s disease
Wang, B., Shi, J., Ge, N.-N., Ou, Z., Tian, Y., Jiang, T., Zhou, J., Xu, J. L., & Zhang, Y.-D. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1178-5 · Cited by 133
“The second signal results in the assembly of the NLRP3 inflammasome, caspase-1 activation, and IL-1β secretion [13].”
Background
A natural products solution to diabetic nephropathy therapy
Hu, Q., Jiang, L., Qi, Y., Zeng, J., Ma, X., & Zhao, Y. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2022.108314 · Cited by 137
Fluoxetine Inhibits NLRP3 Inflammasome Activation: Implication in Depression
Du, R., Tan, J., Sun, X., Lu, M., Ding, J., & Hu, G. (2016) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyw037 · Cited by 128
“*P .05, **P .01 vs CMS. inflammasome to induce caspase-1 cleavage, leading to the maturation of the proinflammatory cytokines IL-1β and IL-18 (Schroder and Tschopp, 2014).”
BackgroundInfluential
Specific inhibition of the NLRP3 inflammasome suppresses immune overactivation and alleviates COVID-19 like pathology in mice
Zeng, J., Xie, X., Feng, X., Xu, L., Han, J.-B., Yu, D., Zou, Q., Liu, Q., Li, X., Ma, G., et al. (2021) · EBioMedicine · doi:10.1016/j.ebiom.2021.103803 · Cited by 130
Curcumin relieves depressive-like behaviors via inhibition of the NLRP3 inflammasome and kynurenine pathway in rats suffering from chronic unpredictable mild stress
Zhang, W., Guo, Y., Han, W., Yang, M., Wen, L., Wang, K., & Jiang, P. (2018) · International Immunopharmacology · doi:10.1016/j.intimp.2018.12.012 · Cited by 128
The Interplay between Obesity and Inflammation
Săvulescu-Fiedler, I., Mihalcea, R., Dragosloveanu, Ş., Scheau, C., Baz, R. O., Căruntu, A., Scheau, A.-E., Căruntu, C., & Benea, S. N. (2024) · Life · doi:10.3390/life14070856 · Cited by 138
Regulatory Roles of Flavonoids on Inflammasome Activation during Inflammatory Responses
Yi, Y. (2018) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201800147 · Cited by 116
Inflammatory Mediators of Endothelial Dysfunction
Dri, E., Lampas, E., Lazaros, G. A., Lazarou, E., Theofilis, P., Tsioufis, C. P., & Tousoulis, D. (2023) · Life · doi:10.3390/life13061420 · Cited by 132
Monocytes and macrophages: Origin, homing, differentiation, and functionality during inflammation
Dash, S. P., Gupta, S., & Sarangi, P. P. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e29686 · Cited by 124
MicroRNA-9 Inhibits NLRP3 Inflammasome Activation in Human Atherosclerosis Inflammation Cell Models through the JAK1/STAT Signaling Pathway
Wang, Y., Han, Z., Fan, Y., Zhang, J., Chen, K., Gao, L., Zeng, H., Cao, J., & Wang, C. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000470822 · Cited by 113
Targeting the NLRP3 Inflammasome-Related Pathways via Tianeptine Treatment-Suppressed Microglia Polarization to the M1 Phenotype in Lipopolysaccharide-Stimulated Cultures
Ślusarczyk, J., Trojan, E., Głombik, K., Piotrowska, A., Budziszewska, B., Kubera, M., Popiołek-Barczyk, K., Lasoń, W., Mika, J., & Basta‐Kaim, A. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19071965 · Cited by 110
Insights into SGLT2 inhibitor treatment of diabetic cardiomyopathy: focus on the mechanisms
Huang, K., Luo, X., Liao, B., Li, G., & Feng, J. (2023) · Cardiovascular Diabetology · doi:10.1186/s12933-023-01816-5 · Cited by 117
Diagnosis and Management of the Cryopyrin-Associated Periodic Syndromes (CAPS): What Do We Know Today?
Welzel, T., & Kuemmerle-Deschner, J. B. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10010128 · Cited by 109
“For example, small molecule inhibitors targeting NLRP3 directly are one promising drug development [115].”
Background
p38MAPK Signaling Pathway in Osteoarthritis: Pathological and Therapeutic Aspects
Li, Z., Dai, A.-N., Yang, M., Chen, S., Deng, Z., & Li, L.-J. (2022) · Journal of Inflammation Research · doi:10.2147/jir.s348491 · Cited by 95
“For example, MCC950, the NLRP3 Inhibitor, has antiinflammatory and anti-senescence effects on some chronic diseases such as Alzheimer’s disease.(89) In a recent study, Ni et al found that the NLRP3 protein was upregulated in the human and mouse OA cartilage and the intra-articular administration of MCC950 could postpo…”
Background
Targeting NLRP3 Inflammasome in Inflammatory Bowel Disease: Putting out the Fire of Inflammation
Shao, B., Wang, S., Pan, P., Yao, J., Wu, K., Li, Z., Bai, Y., & Linghu, E. (2019) · Inflammation · doi:10.1007/s10753-019-01008-y · Cited by 108
Self-citation
Amentoflavone Affects Epileptogenesis and Exerts Neuroprotective Effects by Inhibiting NLRP3 Inflammasome
Rong, S., Wan, D., Fan, Y., Liu, S., Sun, K., Huo, J., Zhang, P., Li, X., Xie, X., Wang, F., et al. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00856 · Cited by 106
Semaglutide attenuates seizure severity and ameliorates cognitive dysfunction by blocking the NLR family pyrin domain containing 3 inflammasome in pentylenetetrazole‑kindled mice
Wang, L., Ding, J., Zhu, C., Guo, B., Wu, Y., He, W., Li, X., Wang, Y., Li, W., Wang, F., et al. (2021) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2021.5052 · Cited by 109
“The NLRP3 inflammasome results from the assembly of NLR family pyrin domain containing 3 (NLRP3), apoptosis‐asso‐ ciated speck‐like protein (ASC) and caspase‐1 (14), and promotes the secretion of inflammatory cytokines, influencing the pathophysiology of epilepsy (14).”
Background
Nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) and its inhibitors
Lee, S.-Y., & Müller, C. E. (2017) · MedChemComm · doi:10.1039/c7md00015d · Cited by 103
Neuroinflammation Mediated by NLRP3 Inflammasome After Intracerebral Hemorrhage and Potential Therapeutic Targets
Xiao, L., Zheng, H., Li, J., Wang, Q., & Sun, H. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-02082-2 · Cited by 107
Activation of NLRP3 Inflammasome in Inflammatory Bowel Disease: Differences Between Crohn’s Disease and Ulcerative Colitis
Lazaridis, L.-D., Pistiki, A. C., Giamarellos‐Bourboulis, E. J., Georgitsi, M., Damoraki, G., Polymeros, D., Dimitriadis, G., & Τriantafyllou, Κ. (2017) · Digestive Diseases and Sciences · doi:10.1007/s10620-017-4609-8 · Cited by 104
“Recent findings suggest that NLRP3 inflammasome activation may play an important role in the progression of various metabolic disorders, such as type 2 diabetes and atherosclerosis and NLRP3 pathways have been associated with several autoimmune and autoinflammatory disorders including gout, familial Mediterranean feve…”
Background
Spotlight on pyroptosis: role in pathogenesis and therapeutic potential of ocular diseases
Chen, M., Rong, R., & Xia, X. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02547-2 · Cited by 102
Targeting NLRP3 Inflammasome in the Treatment of CNS Diseases
Shao, B., Cao, Q., & Chong, L. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00320 · Cited by 103
Self-citation
Honokiol alleviates LPS-induced acute lung injury by inhibiting NLRP3 inflammasome-mediated pyroptosis via Nrf2 activation in vitro and in vivo
Liu, Y., Zhou, J., Luo, Y., Li, J., Shang, L., Zhou, F., & Yang, S. (2021) · Chinese Medicine · doi:10.1186/s13020-021-00541-z · Cited by 107
Diabetes Mellitus Promotes the Development of Atherosclerosis: The Role of NLRP3
Ye, J., Li, L., Wang, M., Ma, Q., Tian, Y., Zhang, Q., Liu, J., Li, B., Zhang, B., Liu, H., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.900254 · Cited by 110
“MCC950 is an NLRP3 inflammasome-specific inhibitor that inhibits NLRP3 activity by blocking ASC oligomerization and NLRP3 ATP hydrolysis (128).”
Background
Costunolide covalently targets NACHT domain of NLRP3 to inhibit inflammasome activation and alleviate NLRP3-driven inflammatory diseases
Xu, H., Chen, J., Chen, P., Li, W., Shao, J., Hong, S., Wang, Y., Chen, L., Luo, W., & Liang, G. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.09.014 · Cited by 104
Regulation of glycolysis and the Warburg effect in wound healing
Vinaik, R., Barayan, D., Auger, C., Abdullahi, A., & Jeschke, M. G. (2020) · JCI Insight · doi:10.1172/jci.insight.138949 · Cited by 103
Multifunctional Hydrogel Eye Drops for Synergistic Treatment of Ocular Inflammatory Disease
Liu, X., Chen, Z., Bai, J., Li, X., Chen, X., Li, Z., Pan, H., Li, S., Gao, Q., Zhao, N., et al. (2023) · ACS Nano · doi:10.1021/acsnano.3c08869 · Cited by 98
NLRP3 Inflammasome Activation: A Therapeutic Target for Cerebral Ischemia–Reperfusion Injury
Wang, L., Ren, W., Wu, Q., Liu, T., Wei, Y. L., Ding, J., Zhou, C., Xu, H., & Yang, S. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.847440 · Cited by 105
Recent advances in the NEK7-licensed NLRP3 inflammasome activation: Mechanisms, role in diseases and related inhibitors
Zhao, N., Li, C.-C., Di, B., & Xu, L.-L. (2020) · Journal of Autoimmunity · doi:10.1016/j.jaut.2020.102515 · Cited by 103
Inhibition of NLRP3 Inflammasome Pathway by Butyrate Improves Corneal Wound Healing in Corneal Alkali Burn
Bian, F., Xiao, Y., Zaheer, M., Volpe, E. A., Pflugfelder, S. C., Li, D., & de Paiva, C. S. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18030562 · Cited by 98
Celastrol inhibits rheumatoid arthritis through the ROS-NF-κB-NLRP3 inflammasome axis
Jing, M. X., Yang, J., Zhang, L., Liu, J., Xu, S., Wang, M., Zhang, L., Sun, Y. M., Yan, W.-B., Hou, G., et al. (2021) · International Immunopharmacology · doi:10.1016/j.intimp.2021.107879 · Cited by 100
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Oral NLRP3 Inflammasome Inhibitor ZYIL1: First‐in‐Human Phase 1 Studies (Single Ascending Dose and Multiple Ascending Dose)
Parmar, D., Kansagra, K., Momin, T., Patel, H. B., Jansari, G. A., Bhavsar, J., Shah, C., Patel, J., Ghoghari, A., Barot, A., et al. (2022) · Clinical pharmacology in drug development · doi:10.1002/cpdd.1162 · Cited by 77
Blockade of Autophagy Prevents the Progression of Hyperuricemic Nephropathy Through Inhibiting NLRP3 Inflammasome-Mediated Pyroptosis
Hu, Y., Shi, Y., Chen, H., Tao, M., Zhou, X., Li, J., Ma, X., Wang, Y., & Liu, N. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.858494 · Cited by 98
NLR-Dependent Regulation of Inflammation in Multiple Sclerosis
Gharagozloo, M., Gris, K. V., Mahvelati, T. M., Amrani, A., Lukens, J. R., & Gris, D. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2017.02012 · Cited by 98
“The activation of proinflammatory NLRs, such as NLRP1, NLRP3, NLRP6, NLRP7, NLRP12, NLRC4, and NAIP has been reported to result in the formation of inflammasome and production of potent inflammatory cytokines, such as IL-1β and IL-18 (78, 79).”
BackgroundInfluential
Role of the inflammasome in chronic obstructive pulmonary disease (COPD)
Colarusso, C., Terlizzi, M., Molino, A., Pinto, A., & Sorrentino, R. (2017) · Oncotarget · doi:10.18632/oncotarget.17850 · Cited by 94
“NOD1 and NOD2) present within the cytoplasm (Figure 1) [5].”
Background
Bronchial epithelial pyroptosis promotes airway inflammation in a murine model of toluene diisocyanate-induced asthma
Zhuang, J., Cui, H., Zhuang, L., Zhai, Z., Yang, F., Luo, G., He, J., Zhao, H., Zhao, W., He, Y., et al. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.109925 · Cited by 88
Advances in the molecular mechanisms of NLRP3 inflammasome activators and inactivators
Liu, D., Zeng, X., Li, X., Cui, C., Hou, R., Guo, Z., Mehta, J. L., & Wang, X. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.113863 · Cited by 88
Astragaloside IV Suppresses High Glucose-Induced NLRP3 Inflammasome Activation by Inhibiting TLR4/NF- κ B and CaSR
Leng, B., Zhang, Y., Liu, X., Zhang, Z., Liu, Y., Wang, H., & Lü, M. (2019) · Mediators of Inflammation · doi:10.1155/2019/1082497 · Cited by 87
NLRP3 inflammasome as a treatment target in atherosclerosis: A focus on statin therapy
Parsamanesh, N., Moossavi, M., Bahrami, A., Fereidouni, M., Barreto, G. E., & Sahebkar, A. (2019) · International Immunopharmacology · doi:10.1016/j.intimp.2019.05.006 · Cited by 87
Ursolic acid protects chondrocytes, exhibits anti-inflammatory properties via regulation of the NF-κB/NLRP3 inflammasome pathway and ameliorates osteoarthritis.
Wang, C., Gao, Y., Zhang, Z., Chen, C., Chi, Q.-J., Xu, K., & Yang, L. (2020) · Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · doi:10.1016/j.biopha.2020.110568 · Cited by 88
Inherent P2X7 Receptors Regulate Macrophage Functions during Inflammatory Diseases
Ren, W.-J., Rubini, P., Tang, Y., Engel, T., & Illés, P. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms23010232 · Cited by 70
The Role of NLRP3 Inflammasome in Cerebrovascular Diseases Pathology and Possible Therapeutic Targets
Bai, R., Lang, Y., Shao, J., Deng, Y., Refuhati, R., & Cui, L. (2021) · ASN NEURO · doi:10.1177/17590914211018100 · Cited by 86
“a) Potassium efflux, considered the most crucial; b) ROS induced by DAMPs or PAMPs; c) Cathepsin B released by lysosomes (Shao et al., 2015).”
Background
Inflammasomes: Pandora’s box for sepsis
Kumar, V. (2018) · Journal of Inflammation Research · doi:10.2147/jir.s178084 · Cited by 88
Inhibition of the NOD-Like Receptor Protein 3 Inflammasome Is Protective in Juvenile Influenza A Virus Infection
Coates, B. M., Staricha, K. L., Ravindran, N., Koch, C. M., Cheng, Y., Davis, J. M., Shumaker, D. K., & Ridge, K. M. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00782 · Cited by 81

Authors: Shao, B.-Z., Xu, Z.-Q., Han, B.-Z., Su, D.-F., & Liu, C.
Affiliations: Second Military Medical University (CN)
Corresponding author: Liu, Chong
ORCID: Shao, Bo-Zong
Su, Ding-Feng
Liu, Chong
Venue: Frontiers in Pharmacology
Publisher: Frontiers Media SA
Published: 2015-11-05
Volume: 6
Pages: 262-262
ISSN: 1663-9812 (ISSN-L)
DOI: 10.3389/fphar.2015.00262
PMC: PMC4633676
OpenAlex: W2137444266
Cited by: 836
References: 115
Citations by year: 2026: 42 · 2025: 62 · 2024: 102 · 2023: 107 · 2022: 114 · 2021: 105 · 2020: 91 · 2019: 68 · 2018: 61 · 2017: 57 · 2016: 24 · 2015: 2
FWCI: 4.60
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
Locations: Frontiers in Pharmacology (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Frontiers in Pharmacology (cc-by)
Funders: Natural Science Foundation of Shanghai (13ZR1448400)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
Keywords: NLRP3 inflammasome, inflammasome inhibitors, innate immunity, autoinflammatory disease, autoimmune disease, metabolic disorders, multiple sclerosis, inflammatory bowel disease

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NLRP3 inflammasome and its inhibitors: a review

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