Oncotarget

Research Papers:

Asiatic acid protects against hepatic ischemia/reperfusion injury by inactivation of Kupffer cells via PPARγ/NLRP3 inflammasome signaling pathway

Ying Xu, Jun Yao, Chen Zou, Heng Zhang, Shouliang Zhang, Jun Liu, Gui Ma, Pengcheng Jiang _ and Wenbo Zhang

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Oncotarget. 2017; 8:86339-86355. https://doi.org/10.18632/oncotarget.21151

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Abstract

Ying Xu1,*, Jun Yao2,*, Chen Zou3, Heng Zhang3, Shouliang Zhang3, Jun Liu3, Gui Ma3, Pengcheng Jiang3 and Wenbo Zhang3

1Department of Laboratory Center, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, China

2Department of Gastroenterology, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, China

3Department of General Surgery, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, China

*These authors have contributed equally to this work

Correspondence to:

Pengcheng Jiang, email: [email protected]

Wenbo Zhang, email: [email protected]

Keywords: asiatic acid, NLRP3 inflammasome, PPARγ, hepatic I/R injury, Kupffer cell

Received: November 30, 2016    Accepted: August 21, 2017    Published: September 21, 2017

ABSTRACT

Hepatic ischemia/reperfusion (I/R) contributes to major complications in clinical practice affecting perioperative morbidity and mortality. Recent evidence suggests the key role of nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammaosme activation on the pathogenesis of I/R injury. Asiatic acid (AA) is a pentacyclic triterpene derivative presented with versatile activities, including antioxidant, anti-inflammation and hepatoprotective effects. This study was designed to determine whether AA had potential hepatoprotective benefits against hepatic I/R injury, as well as to unveil the underlying mechanisms involved in the putative effects. Mice subjected to warm hepatic I/R, and Kupffer cells (KCs) or RAW264.7 cells challenged with lipopolysaccharide (LPS)/H2O2, were pretreated with AA. Administration of AA significantly attenuated hepatic histopathological damage, global inflammatory level, apoptotic signaling level, as well as NLRP3 inflammasome activation. These effects were correlated with increased expression of peroxisome proliferator-activated receptor gamma (PPARγ). Conversely, pharmacological inhibition of PPARγ by GW9662 abolished the protective effects of AA on hepatic I/R injury and in turn aggravated NLRP3 inflammasome activation. Activation of NLRP3 inflammasome was most significant in nonparenchymal cells (NPCs). Depletion of KCs by gadolinium chloride (GdCl3) further attenuated the detrimental effects of GW9662 on hepatic I/R as well as NLRP3 activation. In vitro, AA concentration-dependently inhibited LPS/H2O2-induced NLRP3 inflammaosome activation in KCs and RAW264.7 cells. Either GW9662 or genetic knockdown of PPARγ abolished the AA-mediated inactivation of NLRP3 inflammasome. Mechanistically, AA attenuated I/R or LPS/H2O2-induced ROS production and phosphorylation level of JNK, p38 MAPK and IκBα but not ERK, a mechanism dependent on PPARγ. Finally, AA blocked the deleterious effects of LPS/H2O2-induced macrophage activation on hepatocyte viability in vitro, and improved survival in a lethal hepatic I/R injury model in vivo. Collectively, these data suggest that AA is effective in mitigating hepatic I/R injury through attenuation of KCs activation via PPARγ/NLRP3 inflammasome signaling pathway.


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