The Role of NLRP3 Inflammasome in Type 2 Diabetes Mellitus and Its Macrovascular Complications
Abstract
1. Introduction
2. Search Methodology
3. The NLRP3 Inflammasome; Structure and Activation
4. Regulation of T2DM by NLRP3 Inflammasome
5. NLRP3 Inflammasome and Diabetic Macrovascular Disease
6. NLRP3 Inflammasome-Targeted Pharmacotherapy
6.1. MCC950
6.2. Glyburide Derivatives
6.3. Bay 11-7082
6.4. OLT1177
6.5. Colchicine
6.6. CY-09
6.7. Tranilast
6.8. INF4E
6.9. Hydrogen Sulfide Donors
7. Off-Target Modulation of the NLRP3 Inflammasome by Conventional Drugs and Natural Compounds
7.1. Diabetic Medications and NLRP3 Modulation
7.2. Other Pharmaceutical Agents
7.3. Natural Compounds and Derivatives
8. Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
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Authors | Year | Population | Study | Findings |
---|---|---|---|---|
Esser et al. [25] | 2013 | Human participants with different obesity phenotypes | Cross-sectional observational study | Increased expression of NLRP3 and IL1B in visceral adipose tissue from metabolically unhealthy obese patients |
Yin et al. [26] | 2014 | Postmenopausal women, both lean and obese, undergoing elective abdominal surgery | Cross-sectional observational study | Genes associated with the NOD-like receptor pathway, including the NLRP3, were upregulated in adipocytes from obese individuals |
Wang et al. [27] | 2015 | db/db mice | Pre-clinical experimental study (with in vivo and vitro methodologies) | NLRP3 and Caspase-1 expressions were increased in epididymal fat from db/db mice |
Finucane et al. [28] | 2015 | C57BL/6 mice | Pre-clinical experimental study | NLRP3, Caspase-1, and IL1B expressions in adipose tissue were higher in mice treated for 6 months with a saturated fatty acid HFD in comparison with mice fed with a monounsaturated fatty acid HFD |
Bitto et al. [29] | 2014 | db/db mice | Pre-clinical experimental study | NLRP3, ASC, caspase-1, IL-18, and IL-1 are upregulated during wound healing in animal models of T2DM in comparison with healthy animals |
Coll et al. [30] | 2019 | Mouse bone marrow-derived macrophages and human monocyte-derived macrophages | Pre-clinical experimental study | MCC950, which inhibits the NLRP3 inflammasome, can be applied as a potential anti-inflammatory therapy in T2DM |
Henriksbo et al. [31] | 2014 | ob/ob mice, 3T3-L1 adipocytes (murine adipocyte cell line) | Pre-clinical experimental study (with in vivo and vitro methodologies) | Fluvastatin provokes inflammation and insulin resistance in adipose tissue via the upregulation of NLRP3, which is consistent with the increased expression of NLRP3 in inflamed adipose tissues of T2DM patients |
Kim et al. [32] | 2016 | Murine macrophage cell lines(iJ774) and bone marrow-derived macrophages | Pre-clinical experimental study (with in vivo and vitro methodologies) | NLRP3 can be suppressed by γ-tocotrienol, delaying the progression of T2DM |
Authors | Year | Population | Study | Findings |
---|---|---|---|---|
Ridker et al. CANTOS trial [45] | 2017 | Patients with history of myocardial infarction and elevated hsCRP levels | Randomized, double-blind, placebo controlled, multicenter clinical trial | In total, 150 mg of Canakinumab significantly reduced cardiovascular death, providing the first definitive clinical evidence that reducing inflammation can lower CVD event risk |
Yin Jin et al. [46] | 2022 | ApoE-/– mice | Pre-clinical experimental study | Targeting caspase-1 and the NLRP3 assembly may offer therapeutic potential in atherosclerotic cardiovascular diseases. |
Lee et al. [47] | 2013 | Patients with untreated T2DM | Comparative experimental study | Increased expression of the inflammasome components NLRP3 and ASC was found in monocytes from newly identified, untreated type 2 DM subjects |
Luo et al. [48] | 2014 | HFD and STZ induced rat models | Pre-clinical experimental study | Diabetic rats showed severe metabolic disorder, cardiac inflammation, cell death, disorganized ultrastructure, fibrosis, and excessive activation of NLRP3 |
Wan et al. [49] | 2019 | Humans and ApoE-/– mice | Pre-clinical experimental study (with in vivo and vitro methodologies) | NLRP3 was involved in hyperglycemia-induced endothelial inflammation, both in vitro and in vivo |
Xiao-Xue Li et al. [50] | 2019 | Diabetic rats | Pre-clinical experimental study | High glucose induced the assembly and activation of NLRP3 inflammasome in endothelial cells |
Feng et al. [39] | 2016 | Rat glomerular mesangial cells | Pre-clinical experimental study | High glucose levels and LPS exposure prime the NRLP3 inflammasome in mesangial cells through the ROS/TXNIP signaling pathway, leading to diabetic nephropathy |
Sun et al. [51] | 2019 | STZ-induced diabetic rat model | Pre-clinical experimental study | Suppression of TXNIP/NLRP3 activation ameliorates diabetic peripheral neuropathy |
Yu Li et al. [52] | 2013 | Porcine model of atherosclerosis and DM | Pre-clinical experimental in vivo study | In vivo evidence that the dysregulation of SIRT1-AMPK-SREBP and stimulation of NLRP3 inflammasome may contribute to vascular lipid deposition and inflammation in atherosclerosis |
Duewell et al. [53] | 2010 | Mice deficient in components of the NLRP3 inflammasome | Pre-clinical experimental study (with in vivo and vitro methodologies) | Crystalline cholesterol acts as an endogenous danger signal and its deposition in arteries or elsewhere is an early cause rather than a late consequence of NLRP3 activation and inflammation |
Kirii et al. [54] | 2003 | apoE-/– and IL-1β-/– mice | Pre-clinical experimental in vivo study | IL-1β deficiency significantly reduced atherosclerotic lesion size in the aorta, suggesting that IL-1β promotes atherogenesis through both immune cell recruitment and endothelial activation |
Qian An et al. [55] | 2017 | STZ-induced diabetic rats | Pre-clinical experimental in vivo study | Suppression of the NLRP3 inflammasome pathway via oleanolic acid attenuates carotid artery injury in diabetic rats |
Song et al. [56] | 2015 | Cultured endothelial cells | Experimental in vitro cellular study | Inhibition of ER stress-associated TXNIP/NLRP3 inflammasome activation in endothelial cells improves endothelial homeostasis |
Drugs | Mechanism of Action | Studies | Findings | Status | |
---|---|---|---|---|---|
NLRP3 inhibitors | MCC950 [67,68,69] | Non-covalent bonding to the NACHT domain | Many murine models (HFD, streptozotocin-induced ApoE-/– mice, etc.) and Humans | Reduced atherosclerotic plaque development, decreased the expression of adhesion molecules within the plaque, and lowered the number of macrophages present in the plaque | Clinical development was discontinued due to excessive renal inflammation and hepatic toxicity |
Glyburide [70,71,72] | Inhibition of ATP-dependent potassium channels | Murine and humans models | Suppressed cardiac caspase-1 activity and minimized infarct size in mice undergoing myocardial ischemia followed by 24 h of reperfusion | Limited clinical use due to frequent hypoglycemia | |
Bay 11-7082 [73,74] | NF-κΒ pathway inhibition | Myocardial ischemia–reperfusion murine models | Decreases leukocyte infiltration in the infarcted area and enhances cardiomyocyte survival, reducing infarct size | Pre-clinical studies | |
OLT1177 [75,76,77] | Impairs ATPase activity of NLRP3 | Animal models of myocardial ischemia–reperfusion | Dose-dependent reduction in infarct size, and also improved ventricular function in a model of permanent coronary artery occlusion | Pre-clinical studies | |
Colchicine [78,79,80,81] | Interferes with the NLRP3 complex by disrupting microtubule action | Human studies (COLCOT, LoDoCo) and mouse models of permanent cardiac ligation | Decreased the infiltration of neutrophils and macrophages, as well as the mRNA expression of pro-inflammatory cytokines and NLRP3 inflammasome components 24 h after myocardial infarction | FDA-approved for inflammatory diseases | |
CY-09 [12,82] | Inhibition of the NLRP3 complex by binding directly to the ATP-binding motif of the NACHT domain | Murine models of type 2 Diabetes Mellitus | Prevented cardiac dysfunction linked to diabetic ischemic stroke | Pre-clinical studies | |
Tranilast [71,83,84] | Blocks the direct NLRP3-NLRP3 and NLRP3–ASC interaction | Mouse models of atherosclerosis and several animal models of hypertension, diabetic cardiomyopathy, and myocardial infarction | Enhanced NLRP3 ubiquitination, restricting NLRP3 inflammasome assembly and thereby reducing the initiation and progression of atherosclerotic plaques | Pre-clinical studies | |
INF4E [85,86] | Inhibition of the NLRP3 ATPase activity | Murine models of myocardial ischemia | Reduced infarct size and improved left ventricular pressure | Clinical development was discontinued due to cytotoxic properties | |
Hydrogen Sulfide [14,87] | Reduces NLRP3-dependent caspase-1 activation | Murine specimen undergoing ischemia–reperfusion injury | Diminished the IKKβ/NF-κB signaling pathway introducing cardioprotective properties in a hemorrhagic shock model | Pre-clinical studies | |
Anti-Diabetic Drugs | Metformin [8,47] | Activates AMPK that reduces ER stress and mitochondrial fission leading to inhibition of caspase-1 | Studies in Monocyte-derived macrophages isolated from type 2 diabetic subjects | Protective properties against cell pyroptosis and myocardial ischemia–reperfusion injury by interfering with the AMPK/TOR signaling pathway | FDA-approved for Type-2 diabetes mellitus |
SGLT2 inhibitors [88,89] | Modulatory effects on the AMPK/TOR pathway | Eight-week-old BTBR and wild-type mice | Improved left ventricular end-systolic and end-diastolic volumes, as well as the left ventricular ejection fraction by modulating the AMPK/TOR pathway | FDA-approved for Type-2 diabetes mellitus and heart failure | |
Pioglitazone [90] | Downregulation of NF-κB | apoE (-/–) mice | Reduced ROS releases and attenuated renal damage | FDA-approved for Type-2 diabetes mellitus | |
Acarbose [91] | Inhibition of NOX4-depedant superoxide production | Rats with T2D | Enhanced endothelial function in the aorta of diabetic rats | FDA-approved for Type-2 diabetes mellitus | |
Saxagliptin [8] | AMPK-dependent caspase-1 inhibition | Type 2 diabetic (BTBR ob/ob) and wild-type (WT) mice | Mitigate the advancement of diabetic cardiomyopathy | FDA-approved for Type-2 diabetes mellitus | |
Other pharmaceutical options | Eplerenone [92] | Inhibits phosphorylation of NF-κB and ROS production | C57BL/6 mice fed a high-fat diet (HFD) | Exhibited robust anti-inflammatory properties | FDA-approved drug for hypertension and heart failure |
Verapamil [8] | Inhibits the assembly of NLRP3, reduces the release of IL-1β | Mouse models with diabetic retinopathy | Attenuated pathological neo-angiogenesis | FDA-approved drug for hypertension and angina pectoris | |
Fenofibrate [93] | Unidentified mechanism of NRLP3 inhibition | Mouse models with Diabetic Retinopathy | Attenuated retinal leukostasis, vascular leakage and the progression of DR | FDA-approved for hypertriglyceridemia | |
Atorvastatin [8,94] | Inhibition of NLRP3 inflammasome via TXNIP | Murine models of diabetic cardiomyopathy | Ameliorated diastolic dysfunction and cardiac fibrosis | FDA-approved lipid-lowering agent | |
β-hydroxybutyrate [95] | Abolishes K+ efflux and reduces ASC oligomerization and speck formation via unknown mechanism | Mouse models of ketogenic diet | Inhibited caspase-1 activation, and reduced neutrophil count and hyperglycemia | Pre-clinical studies | |
Natural Substances | Resveratrol [96,97,98] | Modulation of AMPK signaling pathway | Diabetic murine models | Restriction of inflammation and adipose dysfunction | Pre-clinical studies |
Berberine [99] | Enhances AMPK-dependent autophagy | HFD-fed murine models | Improved insulin sensitivity and glucose tolerance | ||
Parthenolide [17,96] | Impairs ATPase activity of NLRP3, suppresses IκB kinase, and NF-κB | mouse ASC (polyclonal anti-mouse ASC), mouse NLRP3 (polyclonal anti-NLRP3 PYD), mouse caspase-1 p20 (monoclonal anti-mouse caspase-1 p20) | Exhibited anti-inflammatory properties via macrophage blockage | ||
Melatonin [100] | suppresses NF-κB signaling by decreasing NF-κB and p65 protein levels in the cytoplasm and nucleus | HFD-fed murine models | Profound decrease in adipose tissue pyroptosis | ||
Glycyrrhizin (GL) and Isoliquiritigenin (ILG) [96,101] | Inhibits mitogen-activated protein kinase (MAPK) activation | HFD-fed murine models | Diminished Il-1β production and adipose tissue inflammation |
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Karamitsos, K.; Oikonomou, E.; Theofilis, P.; Ikonomidis, I.; Kassi, E.; Lambadiari, V.; Gialafos, E.; Tsatsaragkou, A.; Mystakidi, V.-C.; Zisimos, K.; et al. The Role of NLRP3 Inflammasome in Type 2 Diabetes Mellitus and Its Macrovascular Complications. J. Clin. Med. 2025, 14, 4606. https://doi.org/10.3390/jcm14134606
Karamitsos K, Oikonomou E, Theofilis P, Ikonomidis I, Kassi E, Lambadiari V, Gialafos E, Tsatsaragkou A, Mystakidi V-C, Zisimos K, et al. The Role of NLRP3 Inflammasome in Type 2 Diabetes Mellitus and Its Macrovascular Complications. Journal of Clinical Medicine. 2025; 14(13):4606. https://doi.org/10.3390/jcm14134606
Chicago/Turabian StyleKaramitsos, Konstantinos, Evangelos Oikonomou, Panagiotis Theofilis, Ignatios Ikonomidis, Eva Kassi, Vaia Lambadiari, Elias Gialafos, Aikaterini Tsatsaragkou, Vasiliki-Chara Mystakidi, Konstantinos Zisimos, and et al. 2025. "The Role of NLRP3 Inflammasome in Type 2 Diabetes Mellitus and Its Macrovascular Complications" Journal of Clinical Medicine 14, no. 13: 4606. https://doi.org/10.3390/jcm14134606
APA StyleKaramitsos, K., Oikonomou, E., Theofilis, P., Ikonomidis, I., Kassi, E., Lambadiari, V., Gialafos, E., Tsatsaragkou, A., Mystakidi, V.-C., Zisimos, K., Dimitriadis, K., Tousoulis, D., & Siasos, G. (2025). The Role of NLRP3 Inflammasome in Type 2 Diabetes Mellitus and Its Macrovascular Complications. Journal of Clinical Medicine, 14(13), 4606. https://doi.org/10.3390/jcm14134606