Dataset Information

Spermine Alleviates Acute Liver Injury by Inhibiting Liver-Resident Macrophage Pro-Inflammatory Response Through ATG5-Dependent Autophagy.

ABSTRACT: Liver-resident macrophages (Kupffer cells, KCs) and autophagy play critical roles in the pathogenesis of toxin-induced liver injury. Recent evidence indicates that autophagy can regulate macrophage M1/M2 polarization under different inflammatory conditions. Polyamines, including putrescine, spermidine, and spermine (SPM), are polycations with anti-oxidative, anti-aging, and cell autophagy induction properties. This study aimed to determine the mechanisms by which SPM protects against thioacetamide (TAA)-induced acute liver injury in a mouse model. Pretreatment with SPM significantly alleviated liver injury and reduced intrahepatic inflammation in TAA-induced liver injury compared to controls. SPM markedly inhibited M1 polarization, but promoted M2 polarization of KCs obtained from TAA-exposed livers, as evidenced by decreased IL-1? and iNOS gene induction but increased Arg-1 and Mrc-1 gene induction accompanied by decreased STAT1 activation and increased STAT6 activation. Furthermore, pretreatment with SPM enhanced autophagy, as revealed by increased LC3B-II levels, decreased p62 protein expression, and increased ATG5 protein expression in TAA-treated KCs. Knockdown of ATG5 in SPM-pretreated KCs by siRNA resulted in a significant increase in pro-inflammatory TNF-? and IL-6 secretion and decreased anti-inflammatory IL-10 secretion after TAA treatment, while no significant changes were observed in cytokine production in the TAA treatment alone. Additionally, the effect of SPM on regulation of KC M1/M2 polarization was abolished by ATG5 knockdown in TAA-exposed KCs. Finally, in vivo ATG5 knockdown in KCs abrogated the protective effect of SPM against TAA-induced acute liver injury. Our results indicate that SPM-mediated autophagy inhibits M1 polarization, while promoting M2 polarization of KCs in TAA-treated livers via upregulation of ATG5 expression, leading to attenuated liver injury. This study provides a novel target for the prevention of acute liver injury.

SUBMITTER: Zhou S

PROVIDER: S-EPMC5940752 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Spermine Alleviates Acute Liver Injury by Inhibiting Liver-Resident Macrophage Pro-Inflammatory Response Through ATG5-Dependent Autophagy.

Zhou Shun S Gu Jian J Liu Rui R Wei Song S Wang Qi Q Shen Hongbing H Dai Yifan Y Zhou Haoming H Zhang Feng F Lu Ling L

Frontiers in immunology 20180502

Liver-resident macrophages (Kupffer cells, KCs) and autophagy play critical roles in the pathogenesis of toxin-induced liver injury. Recent evidence indicates that autophagy can regulate macrophage M1/M2 polarization under different inflammatory conditions. Polyamines, including putrescine, spermidine, and spermine (SPM), are polycations with anti-oxidative, anti-aging, and cell autophagy induction properties. This study aimed to determine the mechanisms by which SPM protects against thioacetami ...[more]

PMID: 29770139

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Project description:Background: Anoectochilus roxburghii (Orchidaceae) is a traditional Chinese medicinal herb with anti-inflammatory, antilipemic, liver protective, immunomodulatory, and other pharmacological activities. Kinsenoside (KD), which shows protective effects against a variety types of liver damage, is an active ingredient extracted from A. roxburghii. However, the liver protective effects and potential mechanisms of KD in alcoholic liver disease (ALD) remain unclear. This study aimed to investigate the liver protective activity and potential mechanisms of KD in ALD. Methods: AML12 normal mouse hepatocyte cells were used to detect the protective effect of KD against ethanol-induced cell damage. An alcoholic liver injury model was induced by feeding male C57BL/6J mice with an ethanol-containing liquid diet, in combination with intraperitoneal administration of 5% carbon tetrachloride (CCl4) in olive oil. Mice were divided into control, model, silymarin (positive control), and two KD groups, treated with different doses. After treatment, hematoxylin-eosin and Masson's trichrome staining of liver tissues was performed, and serum alanine aminotransferase (ALT) and aspartate transaminase (AST) levels were determined to assess the protective effect of KD against alcoholic liver injury. Moreover, proteomics techniques were used to explore the potential mechanism of KD action, and ELISA assay, immunohistochemistry, TUNEL assay, and western blotting were used to verify the mechanism. Results: The results showed that KD concentration-dependently reduced ethanol-induced lipid accumulation in AML12 cells. In ALD mice model, the histological examination of liver tissues, combined with the determination of ALT and AST serum levels, demonstrated a protective effect of KD in the alcoholic liver injury mice. In addition, KD treatment markedly enhanced the antioxidant capacity and reduced the endoplasmic reticulum (ER) stress, inflammation, and apoptosis compared with those in the model group. Furthermore, KD increased the phosphorylation level of AMP-activated protein kinase (AMPK), inhibited the mechanistic target of rapamycin, promoted the phosphorylation of ULK1 (Ser555), increased the level of the autophagy marker LC3A/B, and restored ethanol-suppressed autophagic flux, thus activating AMPK-dependent autophagy. Conclusion: This study indicates that KD alleviates alcoholic liver injury by reducing oxidative stress and ER stress, while activating AMPK-dependent autophagy. All results suggested that KD may be a potential therapeutic agent for ALD.

Project description:Although the detrimental effects of diabetes mellitus/hyperglycemia have been observed in many liver disease models, the function and mechanism of hyperglycemia regulating liver-resident macrophages, Kupffer cells (KCs), in thioacetamide (TAA)-induced liver injury remain largely unknown. In this study, we evaluated the role of hyperglycemia in regulating NOD-like receptor family pyrin domain-containing 3 protein (NLRP3) inflammasome activation by inhibiting autophagy induction in KCs in the TAA-induced liver injury model. Type I diabetes/hyperglycemia was induced by streptozotocin treatment. Compared with the control group, hyperglycemic mice exhibited a significant increase in intrahepatic inflammation and liver injury. Enhanced NLRP3 inflammasome activation was detected in KCs from hyperglycemic mice, as shown by increased gene induction and protein levels of NLRP3, cleaved caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain and interleukin-1?, compared with control mice. NLRP3 inhibition by its antagonist CY-09 effectively suppressed inflammasome activation in KCs and attenuated liver injury in hyperglycemic mice. Furthermore, inhibited autophagy activation was revealed by transmission electron microscope detection, decreased LC3B protein expression and p-62 protein degradation in KCs isolated from TAA-stressed hyperglycemic mice. Interestingly, inhibited 5' AMP-activated protein kinase (AMPK) but enhanced mammalian target of rapamycin (mTOR) activation was found in KCs from TAA-stressed hyperglycemic mice. AMPK activation by its agonist 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) or mTOR signaling knockdown by small interfering RNA restored autophagy activation, and subsequently, inhibited NLRP3 inflammasome activation in KCs, leading to ultimately reduced TAA-induced liver injury in the hyperglycemic mice. Our findings demonstrated that hyperglycemia aggravated TAA-induced acute liver injury by promoting liver-resident macrophage NLRP3 inflammasome activation via inhibiting AMPK/mTOR-mediated autophagy. This study provided a novel target for prevention of toxin-induced acute liver injury under hyperglycemia.

Project description:The Japanese diet and the Mediterranean diet are rich in polyamines (spermidine and spermine). Increased polyamine intake elevated blood spermine levels, inhibited aging-associated pro-inflammatory status (increases in lymphocyte function-associated antigen-1 (LFA-1) on immune cells), suppressed aberrant gene methylation and extended the lifespan of mice. To test the effects of increased polyamine intake by humans, 30 healthy male volunteers were asked to eat polyamine-rich and ready-to-eat traditional Japanese food (natto) for 12 months. Natto with high polyamine content was used. Another 27 male volunteers were asked not to change their dietary pattern as a control group. The volunteers' age of intervention and control groups ranged from 40 to 69 years (median 48.9 ± 7.9). Two subjects in the control group subsequently dropped out of the study. The estimated increases in spermidine and spermine intakes were 96.63 ± 47.70 and 22.00 ± 9.56 µmol per day in the intervention group, while no changes were observed in the control group. The mean blood spermine level in the intervention group gradually rose to 1.12 ± 0.29 times the pre-intervention level after 12 months, and were significantly higher (p = 0.019) than those in the control group. Blood spermidine did not increase in either group. LFA-1 on monocytes decreased gradually in the intervention group, and there was an inverse association between changes in spermine concentrations relative to spermidine and changes in LFA-1 levels. Contingency table analysis revealed that the odds ratio to decrease LFA-1 by increased polyamine intake was 3.927 (95% CI 1.116-13.715) (p = 0.032) when the effect of acute inflammation was excluded. The results in the study were similar to those of our animal experiments. Since methylation changes of the entire genome are associated with aging-associated pathologies and our previous studies showed that spermine-induced LFA-1 suppression was associated with the inhibition of aberrant gene methylation, the results suggest that dietary polyamine contributes to human health and longevity.

Dataset Information

Spermine Alleviates Acute Liver Injury by Inhibiting Liver-Resident Macrophage Pro-Inflammatory Response Through ATG5-Dependent Autophagy.

Publications

Spermine Alleviates Acute Liver Injury by Inhibiting Liver-Resident Macrophage Pro-Inflammatory Response Through ATG5-Dependent Autophagy.

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