Melatonin modulates mitophagy, innate immunity and circadian clocks in a model of viral‐induced fulminant hepatic failure

The haemorrhagic disease virus (RHDV) is a non‐cultivable virus that promotes in rabbits an acute disease which accomplishes many characteristics of an animal model of fulminant hepatic failure (FHF). Beneficial effects of melatonin have been reported in RHDV‐infected rabbits. This study investigated whether protection against viral‐derived liver injury by melatonin is associated with modulation of mitophagy, innate immunity and clock signalling. Rabbits were experimentally infected with 2 × 104 haemagglutination units of a RHDV isolate and killed at 18, 24 and 30 hours after infection (hpi). Melatonin (20 mg/kg body weight ip) was administered at 0, 12 and 24 hpi. RHDV infection induced mitophagy, with the presence of a high number of mitophagosomes in hepatocytes and increased expression of mitophagy genes. Greater expression of main innate immune intermediaries and inflammasome components was also found in livers with RHDV‐induced FHF. Both mitophagy and innate immunity activation was significantly hindered by melatonin. FHF induction also elicited an early dysregulation in clock signalling, and melatonin was able to prevent such circadian disruption. Our study discloses novel molecular routes contributing to RHDV‐induced damage progression and supports the potential of melatonin as a promising therapeutic option in human FHF.

[1]  A. Franchitto,et al.  Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies , 2020, Journal of pineal research.

[2]  Wei Zhao,et al.  Melatonin attenuates TNF‐α‐mediated hepatocytes damage via inhibiting mitochondrial stress and activating the Akt‐Sirt3 signaling pathway , 2019, Journal of cellular physiology.

[3]  Zhenyu Shen,et al.  Mitophagy protects against acetaminophen-induced acute liver injury in mice through inhibiting NLRP3 inflammasome activation. , 2019, Biochemical pharmacology.

[4]  Xi Chen,et al.  Crocetin protects against fulminant hepatic failure induced by lipopolysaccharide/D-galactosamine by decreasing apoptosis, inflammation and oxidative stress in a rat model , 2019, Experimental and therapeutic medicine.

[5]  D. Yavagal,et al.  Interplay between Mitophagy and Inflammasomes in Neurological Disorders. , 2019, ACS chemical neuroscience.

[6]  Yanning Liu,et al.  AMSC-derived exosomes alleviate lipopolysaccharide/d-galactosamine-induced acute liver failure by miR-17-mediated reduction of TXNIP/NLRP3 inflammasome activation in macrophages , 2018, EBioMedicine.

[7]  Chunhua Hu,et al.  Role of mitophagy regulation by ROS in hepatic stellate cells during acute liver failure. , 2018, American journal of physiology. Gastrointestinal and liver physiology.

[8]  H. Jaeschke,et al.  Role and mechanisms of autophagy in acetaminophen‐induced liver injury , 2018, Liver international : official journal of the International Association for the Study of the Liver.

[9]  Sean Koppe,et al.  Modern Management of Acute Liver Failure. , 2018, Gastroenterology clinics of North America.

[10]  J. González‐Gallego,et al.  Melatonin Attenuates Dysregulation of the Circadian Clock Pathway in Mice With CCl4-Induced Fibrosis and Human Hepatic Stellate Cells , 2018, Front. Pharmacol..

[11]  J. González‐Gallego,et al.  Melatonin modulates dysregulated circadian clocks in mice with diethylnitrosamine‐induced hepatocellular carcinoma , 2018, Journal of pineal research.

[12]  L. BenMohamed,et al.  The wide utility of rabbits as models of human diseases , 2018, Experimental & Molecular Medicine.

[13]  N. Pyrsopoulos,et al.  Acute Liver Failure: Mechanisms of Disease and Multisystemic Involvement. , 2018, Clinics in liver disease.

[14]  Hongbo Hu,et al.  Mechanisms of acetaminophen-induced liver injury and its implications for therapeutic interventions , 2018, Redox biology.

[15]  A. Loudon,et al.  Circadian clock component REV-ERBα controls homeostatic regulation of pulmonary inflammation , 2018, The Journal of clinical investigation.

[16]  Steven A. Brown,et al.  Circadian Control of DRP1 Activity Regulates Mitochondrial Dynamics and Bioenergetics. , 2018, Cell metabolism.

[17]  Shuncai Zhang,et al.  The Flavonoid Quercetin Ameliorates Liver Inflammation and Fibrosis by Regulating Hepatic Macrophages Activation and Polarization in Mice , 2018, Front. Pharmacol..

[18]  Xiaojun Wu,et al.  Berberine protects acute liver failure in mice through inhibiting inflammation and mitochondria‐dependent apoptosis , 2018, European journal of pharmacology.

[19]  J. Eeckhoute,et al.  Nuclear Receptor Subfamily 1 Group D Member 1 Regulates Circadian Activity of NLRP3 Inflammasome to Reduce the Severity of Fulminant Hepatitis in Mice. , 2017, Gastroenterology.

[20]  A. Loudon,et al.  Clocking in to immunity , 2018, Nature Reviews Immunology.

[21]  Norihiko Furuya.  Short Overview. , 2018, Methods in molecular biology.

[22]  A. Sato,et al.  Rev-erb agonist improves adverse cardiac remodeling and survival in myocardial infarction through an anti-inflammatory mechanism , 2017, PloS one.

[23]  J. McKeating,et al.  Interplay between circadian clock and viral infection , 2017, Journal of Molecular Medicine.

[24]  J. González‐Gallego,et al.  Melatonin enhances sorafenib actions in human hepatocarcinoma cells by inhibiting mTORC1/p70S6K/HIF-1α and hypoxia-mediated mitophagy , 2017, Oncotarget.

[25]  D. Acuña-Castroviejo,et al.  Melatonin, clock genes and mitochondria in sepsis , 2017, Cellular and Molecular Life Sciences.

[26]  H. Jaeschke,et al.  Role of the inflammasome in acetaminophen-induced liver injury and acute liver failure. , 2017, Journal of hepatology.

[27]  Hyo Sun Jin,et al.  Mitochondrial Control of Innate Immunity and Inflammation , 2017, Immune network.

[28]  J. González‐Gallego,et al.  Inhibition of the SphK1/S1P signaling pathway by melatonin in mice with liver fibrosis and human hepatic stellate cells , 2017, BioFactors.

[29]  Sun-Mee Lee,et al.  Afzelin ameliorates D‐galactosamine and lipopolysaccharide‐induced fulminant hepatic failure by modulating mitochondrial quality control and dynamics , 2017, British journal of pharmacology.

[30]  J. González‐Gallego,et al.  Melatonin prevents deregulation of the sphingosine kinase/sphingosine 1‐phosphate signaling pathway in a mouse model of diethylnitrosamine‐induced hepatocellular carcinoma , 2017, Journal of pineal research.

[31]  J. Ryu,et al.  Mitophagy: a balance regulator of NLRP3 inflammasome activation , 2016, BMB reports.

[32]  L. Arasi,et al.  Acute Liver Failure , 2016, AACN advanced critical care.

[33]  R. Ordoñez,et al.  Melatonin‐induced increase in sensitivity of human hepatocellular carcinoma cells to sorafenib is associated with reactive oxygen species production and mitophagy , 2016, Journal of pineal research.

[34]  J. González‐Gallego,et al.  Melatonin inhibits the sphingosine kinase 1/sphingosine‐1‐phosphate signaling pathway in rabbits with fulminant hepatitis of viral origin , 2016, Journal of pineal research.

[35]  Z. Wang,et al.  PER1 prevents excessive innate immune response during endotoxin-induced liver injury through regulation of macrophage recruitment in mice , 2016, Cell death & disease.

[36]  Ana Guerra-Librero,et al.  Same molecule but different expression: aging and sepsis trigger NLRP3 inflammasome activation, a target of melatonin , 2016, Journal of pineal research.

[37]  William B. Mair,et al.  Hepatic Bmal1 Regulates Rhythmic Mitochondrial Dynamics and Promotes Metabolic Fitness. , 2015, Cell metabolism.

[38]  J. González‐Gallego,et al.  Melatonin inhibits autophagy and endoplasmic reticulum stress in mice with carbon tetrachloride‐induced fibrosis , 2015, Journal of pineal research.

[39]  H. Jaeschke,et al.  Chronic Deletion and Acute Knockdown of Parkin Have Differential Responses to Acetaminophen-induced Mitophagy and Liver Injury in Mice* , 2015, The Journal of Biological Chemistry.

[40]  Juanli Fu,et al.  Role of α-lipoic acid in LPS/d-GalN induced fulminant hepatic failure in mice: studies on oxidative stress, inflammation and apoptosis. , 2014, International immunopharmacology.

[41]  J. Prieto,et al.  Melatonin modulates the autophagic response in acute liver failure induced by the rabbit hemorrhagic disease virus , 2014, Journal of pineal research.

[42]  J. Prieto,et al.  Autophagic response in the Rabbit Hemorrhagic Disease, an animal model of virally-induced fulminant hepatic failure , 2014, Veterinary Research.

[43]  J. Prieto,et al.  Melatonin treatment reduces endoplasmic reticulum stress and modulates the unfolded protein response in rabbits with lethal fulminant hepatitis of viral origin , 2013, Journal of pineal research.

[44]  J. Eeckhoute,et al.  Rev-erb-α modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy , 2013, Nature Medicine.

[45]  J. González‐Gallego,et al.  Melatonin attenuates inflammation and promotes regeneration in rabbits with fulminant hepatitis of viral origin , 2012, Journal of pineal research.

[46]  J. Prieto,et al.  Cardiotrophin-1 Promotes a High Survival Rate in Rabbits with Lethal Fulminant Hepatitis of Viral Origin , 2011, Journal of Virology.

[47]  J. Prieto,et al.  Melatonin attenuates apoptotic liver damage in fulminant hepatic failure induced by the rabbit hemorrhagic disease virus , 2011, Journal of pineal research.

[48]  Q. Ning,et al.  Acute liver failure: mechanisms of immune‐mediated liver injury , 2010, Liver international : official journal of the International Association for the Study of the Liver.

[49]  J. González‐Gallego,et al.  Melatonin prevents the decreased activity of antioxidant enzymes and activates nuclear erythroid 2‐related factor 2 signaling in an animal model of fulminant hepatic failure of viral origin , 2010, Journal of pineal research.

[50]  J. González‐Gallego,et al.  Signaling pathways involved in liver injury and regeneration in rabbit hemorrhagic disease, an animal model of virally-induced fulminant hepatic failure , 2009, Veterinary research.

[51]  J. González‐Gallego,et al.  An overview of animal models for investigating the pathogenesis and therapeutic strategies in acute hepatic failure. , 2009, World journal of gastroenterology.

[52]  J. González‐Gallego,et al.  Quercetin administration ameliorates pulmonary complications of cirrhosis in rats. , 2009, The Journal of nutrition.

[53]  J. González‐Gallego,et al.  Melatonin is able to reduce the apoptotic liver changes induced by aging via inhibition of the intrinsic pathway of apoptosis. , 2007, The journals of gerontology. Series A, Biological sciences and medical sciences.

[54]  J. González‐Gallego,et al.  N-acetyl-cysteine protects liver from apoptotic death in an animal model of fulminant hepatic failure , 2006, Apoptosis.

[55]  J. González‐Gallego,et al.  Rabbit hemorrhagic viral disease: characterization of a new animal model of fulminant liver failure. , 2003, The Journal of laboratory and clinical medicine.

[56]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.