Melatonin alleviates cadmium-induced liver injury by inhibiting the TXNIP-NLRP3 inflammasome

Zhengwang Cao, Yiliang Fang, Yonghui Lu, Dunxian Tan, Changhong Du, Yuming Li, Qinlong Ma, Junmei Yu, Mengyan Chen, Chao Zhou, Liping Pei, Lei Zhang, Haiying Ran, Mindi He, Zhengping Yu, Zhou Zhou

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Cadmium (Cd) is a persistent environmental and occupational contaminant that accumulates in the liver and induces oxidative stress and inflammation. Melatonin possesses potent hepatoprotective properties against the development and progression of acute and chronic liver injury. Nevertheless, the molecular mechanism underlying the protective effects of melatonin against Cd-induced hepatotoxicity remains obscure. In this study, we aimed to investigate the effects of melatonin on Cd-induced liver inflammation and hepatocyte death. Male C57BL/6 mice were intraperitoneally injected with melatonin (10 mg/kg) once a day for 3 days before exposure to CdCl2 (2.0 mg/kg). We found that Cd induced hepatocellular damage and inflammatory infiltration as well as increased serum ALT/AST enzymes. In addition, we showed that Cd triggered an inflammatory cell death, which is mediated by the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome. Moreover, melatonin treatment significantly alleviated Cd-induced liver injury by decreasing serum ALT/AST levels, suppressing pro-inflammatory cytokine production, inhibiting NLRP3 inflammasome activation, ameliorating oxidative stress, and attenuating hepatocyte death. Most importantly, melatonin markedly abrogated Cd-induced TXNIP overexpression and decreased the interaction between TXNIP and NLRP3 in vivo and in vitro. However, treatment with siRNA targeting TXNIP blocked the protective effects of melatonin in Cd-treated primary hepatocytes. Collectively, our results suggest that melatonin confers protection against Cd-induced liver inflammation and hepatocyte death via inhibition of the TXNIP-NLRP3 inflammasome pathway.

Original languageEnglish (US)
Article numbere12389
JournalJournal of Pineal Research
Volume62
Issue number3
DOIs
StatePublished - Apr 1 2017

Fingerprint

Inflammasomes
Melatonin
Cadmium
Liver
Wounds and Injuries
Hepatocytes
Inflammation
Oxidative Stress
NLR Proteins
Pyrin Domain
Cadmium Chloride
Serum
Inbred C57BL Mouse
Small Interfering RNA
Cell Death
Cytokines

Keywords

  • cadmium
  • liver injury
  • melatonin
  • NLRP3 inflammasome
  • TXNIP

ASJC Scopus subject areas

  • Endocrinology

Cite this

Melatonin alleviates cadmium-induced liver injury by inhibiting the TXNIP-NLRP3 inflammasome. / Cao, Zhengwang; Fang, Yiliang; Lu, Yonghui; Tan, Dunxian; Du, Changhong; Li, Yuming; Ma, Qinlong; Yu, Junmei; Chen, Mengyan; Zhou, Chao; Pei, Liping; Zhang, Lei; Ran, Haiying; He, Mindi; Yu, Zhengping; Zhou, Zhou.

In: Journal of Pineal Research, Vol. 62, No. 3, e12389, 01.04.2017.

Research output: Contribution to journalArticle

Cao, Z, Fang, Y, Lu, Y, Tan, D, Du, C, Li, Y, Ma, Q, Yu, J, Chen, M, Zhou, C, Pei, L, Zhang, L, Ran, H, He, M, Yu, Z & Zhou, Z 2017, 'Melatonin alleviates cadmium-induced liver injury by inhibiting the TXNIP-NLRP3 inflammasome', Journal of Pineal Research, vol. 62, no. 3, e12389. https://doi.org/10.1111/jpi.12389
Cao, Zhengwang ; Fang, Yiliang ; Lu, Yonghui ; Tan, Dunxian ; Du, Changhong ; Li, Yuming ; Ma, Qinlong ; Yu, Junmei ; Chen, Mengyan ; Zhou, Chao ; Pei, Liping ; Zhang, Lei ; Ran, Haiying ; He, Mindi ; Yu, Zhengping ; Zhou, Zhou. / Melatonin alleviates cadmium-induced liver injury by inhibiting the TXNIP-NLRP3 inflammasome. In: Journal of Pineal Research. 2017 ; Vol. 62, No. 3.
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AU - Tan, Dunxian

AU - Du, Changhong

AU - Li, Yuming

AU - Ma, Qinlong

AU - Yu, Junmei

AU - Chen, Mengyan

AU - Zhou, Chao

AU - Pei, Liping

AU - Zhang, Lei

AU - Ran, Haiying

AU - He, Mindi

AU - Yu, Zhengping

AU - Zhou, Zhou

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N2 - Cadmium (Cd) is a persistent environmental and occupational contaminant that accumulates in the liver and induces oxidative stress and inflammation. Melatonin possesses potent hepatoprotective properties against the development and progression of acute and chronic liver injury. Nevertheless, the molecular mechanism underlying the protective effects of melatonin against Cd-induced hepatotoxicity remains obscure. In this study, we aimed to investigate the effects of melatonin on Cd-induced liver inflammation and hepatocyte death. Male C57BL/6 mice were intraperitoneally injected with melatonin (10 mg/kg) once a day for 3 days before exposure to CdCl2 (2.0 mg/kg). We found that Cd induced hepatocellular damage and inflammatory infiltration as well as increased serum ALT/AST enzymes. In addition, we showed that Cd triggered an inflammatory cell death, which is mediated by the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome. Moreover, melatonin treatment significantly alleviated Cd-induced liver injury by decreasing serum ALT/AST levels, suppressing pro-inflammatory cytokine production, inhibiting NLRP3 inflammasome activation, ameliorating oxidative stress, and attenuating hepatocyte death. Most importantly, melatonin markedly abrogated Cd-induced TXNIP overexpression and decreased the interaction between TXNIP and NLRP3 in vivo and in vitro. However, treatment with siRNA targeting TXNIP blocked the protective effects of melatonin in Cd-treated primary hepatocytes. Collectively, our results suggest that melatonin confers protection against Cd-induced liver inflammation and hepatocyte death via inhibition of the TXNIP-NLRP3 inflammasome pathway.

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