Melatonin Suppresses NLRP3 Inflammasome Activation Via TLR4/NF-κB and P2X7R Signaling in High-Fat Diet-Induced Murine NASH Model

Overview

Journal J Inflamm Res

Publisher Dove Medical Press

Date 2022 Jun 7

PMID 35668917

Authors

Moumita Saha

Krishnendu Manna

Krishna Das Saha

Affiliations

Soon will be listed here.

Abstract

Background: NLRP3 inflammasome activation plays a critical role in mediating inflammation and NASH (non-alcoholic steatohepatitis) progression that ultimately leads to cirrhosis and hepatocellular carcinoma. Melatonin (MLT) controls high-fat diet-induced NASH in the murine model by modulating NLRP3 mediated inflammation. P2X7R-mediated inflammasome activation is reported in several inflammatory models including NASH.

Objective: The role of MLT in P2X7R-mediated inflammation in the NASH model has not yet been explored. The present study investigated the role of MLT in amending high-fat diet-induced nonalcoholic steatohepatitis in the murine liver.

Methods: To evaluate the hepatological changes, mice were divided into four groups to investigate the improvement potential of this MLT (10 and 20 mg/kg) and to assess the experimental findings. Histology, biochemical assays, ELISA, FACS analysis, Western blotting, and IF were performed to assess the physical and molecular changes upon melatonin treatment.

Results: The result demonstrated that MLT administration reduced HFD (high-fat diet)-induced non-alcoholic steatohepatitic indices, which successively restored the hepatic morphological architecture and other pathophysiological features too. Moreover, the application of MLT suppressed HFD-induced activation of the inflammasome and through TLR4/NF-κB signaling. Herein, we report that MLT significantly suppresses P2X7R expression and calcium influx along with inflammasome in both in vitro and in vivo. The docking study revealed a strong binding affinity of MLT with P2X7R. Moreover, the results also showed that the Nrf2 level was boosted which may normalize the expression of antioxidant proteins that safeguard against oxidative damage triggered by inflammation. Furthermore, some matrix metalloproteinases like MMP 2 and MMP 9 were repressed and TIMP-1 level was increased, which also signifies that MLT could improve liver fibrosis in this model.

Conclusion: Based on our findings, this study may conclude that MLT could be used as a therapeutic agent in the high-fat diet-induced NASH model as it has persuasive anti-inflammatory potential.

Citing Articles

Alterations in Glutathione Redox Homeostasis in Metabolic Dysfunction-Associated Fatty Liver Disease: A Systematic Review.

Cesarini L, Grignaffini F, Alisi A, Pastore A Antioxidants (Basel). 2025; 13(12.

PMID: 39765791 PMC: 11672975. DOI: 10.3390/antiox13121461.

Melatonin's Impact on Cytokine Storm and Modulation of Purinergic Receptors for COVID-19 Prognosis: A Mental Health Perspective.

Bertollo A, Dalazen J, Cassol J, Hellmann M, Mota T, Ignacio Z J Mol Neurosci. 2024; 74(4):113.

PMID: 39636363 DOI: 10.1007/s12031-024-02292-6.

Antagonism of the ATP-gated P2X7 receptor inhibits the proliferation of hepatocellular carcinoma cells.

Tantai X, Yang X, Liu X, Yang X Purinergic Signal. 2024; .

PMID: 39549156 DOI: 10.1007/s11302-024-10064-5.

Melatonin and retinal cell damage: molecular and biological functions.

Sun J, Liu Y, Chen Z Naunyn Schmiedebergs Arch Pharmacol. 2024; .

PMID: 39520554 DOI: 10.1007/s00210-024-03575-w.

Melatonin Ameliorates Hepatic Ferroptosis in NAFLD by Inhibiting ER Stress via the MT2/cAMP/PKA/IRE1 Signaling Pathway.

Guan Q, Wang Z, Hu K, Cao J, Dong Y, Chen Y Int J Biol Sci. 2023; 19(12):3937-3950.

PMID: 37564204 PMC: 10411470. DOI: 10.7150/ijbs.85883.

References

Kong F, Ye B, Cao J, Cai X, Lin L, Huang S . Curcumin Represses NLRP3 Inflammasome Activation via TLR4/MyD88/NF-κB and P2X7R Signaling in PMA-Induced Macrophages. Front Pharmacol. 2016; 7:369. PMC: 5056188. DOI: 10.3389/fphar.2016.00369. View

Boppidi H, Daram S . Nonalcoholic fatty liver disease: hepatic manifestation of obesity and the metabolic syndrome. Postgrad Med. 2008; 120(2):E01-7. DOI: 10.3810/pgm.2008.07.1800. View

Liu Y, Li C, Yin H, Zhang X, Li Y . NLRP3 Inflammasome: A Potential Alternative Therapy Target for Atherosclerosis. Evid Based Complement Alternat Med. 2020; 2020:1561342. PMC: 7150718. DOI: 10.1155/2020/1561342. View

Pandey N, Renwick J, Rabaa S, Misquith A, Kouri L, Twomey E . An induction in hepatic HDL secretion associated with reduced ATPase expression. Am J Pathol. 2009; 175(4):1777-87. PMC: 2751572. DOI: 10.2353/ajpath.2009.090082. View

Buzzetti E, Pinzani M, Tsochatzis E . The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism. 2016; 65(8):1038-48. DOI: 10.1016/j.metabol.2015.12.012. View

Wree A, McGeough M, Pena C, Schlattjan M, Li H, Inzaugarat M . NLRP3 inflammasome activation is required for fibrosis development in NAFLD. J Mol Med (Berl). 2014; 92(10):1069-82. PMC: 4349416. DOI: 10.1007/s00109-014-1170-1. View

Weber K, Schilling J . Lysosomes integrate metabolic-inflammatory cross-talk in primary macrophage inflammasome activation. J Biol Chem. 2014; 289(13):9158-71. PMC: 3979407. DOI: 10.1074/jbc.M113.531202. View

Sayiner M, Koenig A, Henry L, Younossi Z . Epidemiology of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis in the United States and the Rest of the World. Clin Liver Dis. 2016; 20(2):205-14. DOI: 10.1016/j.cld.2015.10.001. View

Naim A, Pan Q, Baig M . Matrix Metalloproteinases (MMPs) in Liver Diseases. J Clin Exp Hepatol. 2017; 7(4):367-372. PMC: 5715451. DOI: 10.1016/j.jceh.2017.09.004. View

10.

Mridha A, Wree A, Robertson A, Yeh M, Johnson C, Van Rooyen D . NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice. J Hepatol. 2017; 66(5):1037-1046. PMC: 6536116. DOI: 10.1016/j.jhep.2017.01.022. View

11.

Friedman S . Mechanisms of hepatic fibrogenesis. Gastroenterology. 2008; 134(6):1655-69. PMC: 2888539. DOI: 10.1053/j.gastro.2008.03.003. View

12.

Tan D, Hardeland R, Manchester L, Paredes S, Korkmaz A, Sainz R . The changing biological roles of melatonin during evolution: from an antioxidant to signals of darkness, sexual selection and fitness. Biol Rev Camb Philos Soc. 2009; 85(3):607-23. DOI: 10.1111/j.1469-185X.2009.00118.x. View

13.

Jackson M, Taylor A, Jones E, Forrester L . The culture of mouse embryonic stem cells and formation of embryoid bodies. Methods Mol Biol. 2010; 633:1-18. DOI: 10.1007/978-1-59745-019-5_1. View

14.

Lochner A, Marais E, Huisamen B . Melatonin and cardioprotection against ischaemia/reperfusion injury: What's new? A review. J Pineal Res. 2018; 65(1):e12490. DOI: 10.1111/jpi.12490. View

15.

Lebeaupin C, Vallee D, Hazari Y, Hetz C, Chevet E, Bailly-Maitre B . Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. J Hepatol. 2018; 69(4):927-947. DOI: 10.1016/j.jhep.2018.06.008. View

16.

Hu W, Ma Z, Jiang S, Fan C, Deng C, Yan X . Melatonin: the dawning of a treatment for fibrosis?. J Pineal Res. 2015; 60(2):121-31. DOI: 10.1111/jpi.12302. View

17.

Karolczak K, Watala C . The Mystery behind the Pineal Gland: Melatonin Affects the Metabolism of Cholesterol. Oxid Med Cell Longev. 2019; 2019:4531865. PMC: 6652030. DOI: 10.1155/2019/4531865. View

18.

Xia M, Liang Y, Wang H, Chen X, Huang Y, Zhang Z . Melatonin modulates TLR4-mediated inflammatory genes through MyD88- and TRIF-dependent signaling pathways in lipopolysaccharide-stimulated RAW264.7 cells. J Pineal Res. 2012; 53(4):325-34. DOI: 10.1111/j.1600-079X.2012.01002.x. View

19.

Sun H, Wang X, Chen J, Song K, Gusdon A, Li L . Melatonin improves non-alcoholic fatty liver disease via MAPK-JNK/P38 signaling in high-fat-diet-induced obese mice. Lipids Health Dis. 2016; 15(1):202. PMC: 5120511. DOI: 10.1186/s12944-016-0370-9. View

20.

Bonomini F, Santos M, Veronese F, Rezzani R . NLRP3 Inflammasome Modulation by Melatonin Supplementation in Chronic Pristane-Induced Lupus Nephritis. Int J Mol Sci. 2019; 20(14). PMC: 6678949. DOI: 10.3390/ijms20143466. View