The ER stress sensor inositol-requiring enzyme 1α in Kupffer cells promotes hepatic ischemia-reperfusion injury
2021; Elsevier BV; Volume: 298; Issue: 1 Linguagem: Inglês
10.1016/j.jbc.2021.101532
ISSN1083-351X
AutoresJie Cai, Xiaoge Zhang, Peng Chen, Yang Li, Songzi Liu, Qian Liu, Hanyong Zhang, Zhuyin Wu, Ke Song, Jianmiao Liu, Bo Shan, Yong Liu,
Tópico(s)Heme Oxygenase-1 and Carbon Monoxide
ResumoHepatic ischemia/reperfusion (I/R) injury is an inflammation-mediated process arising from ischemia/reperfusion-elicited stress in multiple cell types, causing liver damage during surgical procedures and often resulting in liver failure. Endoplasmic reticulum (ER) stress triggers the activation of the unfolded protein response (UPR) and is implicated in tissue injuries, including hepatic I/R injury. However, the cellular mechanism that links the UPR signaling to local inflammatory responses during hepatic I/R injury remains largely obscure. Here, we report that IRE1α, a critical ER-resident transmembrane signal transducer of the UPR, plays an important role in promoting Kupffer-cell-mediated liver inflammation and hepatic I/R injury. Utilizing a mouse model in which IRE1α is specifically ablated in myeloid cells, we found that abrogation of IRE1α markedly attenuated necrosis and cell death in the liver, accompanied by reduced neutrophil infiltration and liver inflammation following hepatic I/R injury. Mechanistic investigations in mice as well as in primary Kupffer cells revealed that loss of IRE1α in Kupffer cells not only blunted the activation of the NLRP3 inflammasome and IL-1β production, but also suppressed the expression of the inducible nitric oxide synthase (iNos) and proinflammatory cytokines. Moreover, pharmacological inhibition of IRE1α′s RNase activity was able to attenuate inflammasome activation and iNos expression in Kupffer cells, leading to alleviation of hepatic I/R injury. Collectively, these results demonstrate that Kupffer cell IRE1α mediates local inflammatory damage during hepatic I/R injury. Our findings suggest that IRE1α RNase activity may serve as a promising target for therapeutic treatment of ischemia/reperfusion-associated liver inflammation and dysfunction. Hepatic ischemia/reperfusion (I/R) injury is an inflammation-mediated process arising from ischemia/reperfusion-elicited stress in multiple cell types, causing liver damage during surgical procedures and often resulting in liver failure. Endoplasmic reticulum (ER) stress triggers the activation of the unfolded protein response (UPR) and is implicated in tissue injuries, including hepatic I/R injury. However, the cellular mechanism that links the UPR signaling to local inflammatory responses during hepatic I/R injury remains largely obscure. Here, we report that IRE1α, a critical ER-resident transmembrane signal transducer of the UPR, plays an important role in promoting Kupffer-cell-mediated liver inflammation and hepatic I/R injury. Utilizing a mouse model in which IRE1α is specifically ablated in myeloid cells, we found that abrogation of IRE1α markedly attenuated necrosis and cell death in the liver, accompanied by reduced neutrophil infiltration and liver inflammation following hepatic I/R injury. Mechanistic investigations in mice as well as in primary Kupffer cells revealed that loss of IRE1α in Kupffer cells not only blunted the activation of the NLRP3 inflammasome and IL-1β production, but also suppressed the expression of the inducible nitric oxide synthase (iNos) and proinflammatory cytokines. Moreover, pharmacological inhibition of IRE1α′s RNase activity was able to attenuate inflammasome activation and iNos expression in Kupffer cells, leading to alleviation of hepatic I/R injury. Collectively, these results demonstrate that Kupffer cell IRE1α mediates local inflammatory damage during hepatic I/R injury. Our findings suggest that IRE1α RNase activity may serve as a promising target for therapeutic treatment of ischemia/reperfusion-associated liver inflammation and dysfunction. Hepatic ischemia/reperfusion (I/R) injury represents one of the major complications occurring during liver resection, transplantation, hypovolemic shock, and other liver surgeries, which causes increased risk of organ rejection and liver dysfunction (1Zhai Y. Petrowsky H. Hong J.C. Busuttil R.W. Kupiec-Weglinski J.W. Ischaemia-reperfusion injury in liver transplantation--From bench to bedside.Nat. Rev. Gastroenterol. Hepatol. 2013; 10: 79-89Crossref PubMed Scopus (461) Google Scholar, 2Rakic M. Patrlj L. Amic F. Aralica G. Grgurevic I. Comparison of hepatoprotective effect from ischemia-reperfusion injury of remote ischemic preconditioning of the liver vs local ischemic preconditioning of the liver during human liver resections.Int. J. 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Immunol. 2013; 191: 2665-2679Crossref PubMed Scopus (150) Google Scholar). Hepatic I/R injury is initiated by the ischemic insult that leads to cellular damage and cell death of hepatocytes via oxidative stress and reactive oxygen species (ROS) production, triggering a local sterile immune response characterized by recruitment of Kupffer cells (KCs) and neutrophils. Propagation of the innate and adaptive immune responses in turn results in elevated cytokine production, further aggravating hepatocyte cell death and necrotic damage in the liver (1Zhai Y. Petrowsky H. Hong J.C. Busuttil R.W. Kupiec-Weglinski J.W. Ischaemia-reperfusion injury in liver transplantation--From bench to bedside.Nat. Rev. Gastroenterol. Hepatol. 2013; 10: 79-89Crossref PubMed Scopus (461) Google Scholar, 6Huang H. Chen H.W. Evankovich J. Yan W. Rosborough B.R. Nace G.W. Ding Q. Loughran P. Beer-Stolz D. Billiar T.R. Esmon C.T. Tsung A. 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Comparison of hepatoprotective effect from ischemia-reperfusion injury of remote ischemic preconditioning of the liver vs local ischemic preconditioning of the liver during human liver resections.Int. J. Surg. 2018; 54: 248-253Crossref PubMed Scopus (16) Google Scholar, 3Zhang X.J. Cheng X. Yan Z.Z. Fang J. Wang X. Wang W. Liu Z.Y. Shen L.J. Zhang P. Wang P.X. Liao R. Ji Y.X. Wang J.Y. Tian S. Zhu X.Y. et al.An ALOX12-12-HETE-GPR31 signaling axis is a key mediator of hepatic ischemia-reperfusion injury.Nat. Med. 2018; 24: 73-83Crossref PubMed Scopus (106) Google Scholar, 4Quesnelle K.M. Bystrom P.V. Toledo-Pereyra L.H. Molecular responses to ischemia and reperfusion in the liver.Arch. Toxicol. 2015; 89: 651-657Crossref PubMed Scopus (64) Google Scholar, 5Yang Q. Liu Y. Shi Y. Zheng M. He J. Chen Z. 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To investigate whether the UPR signaling branch is implicated in KC activation in response to hepatic I/R injury, we established the hepatic I/R injury model in mice that were subjected to 60 min of partial warm ischemia followed by 6 h of reperfusion in the liver. Immunoblot analyses revealed elevations in IRE1α phosphorylation as well as in the spliced form of XBP1 (XBP1s) protein level, but no apparent changes in eIF2α phosphorylation in I/R-injured livers relative to their sham control (Fig. 1A). In line with previously reported studies (6Huang H. Chen H.W. Evankovich J. Yan W. Rosborough B.R. Nace G.W. Ding Q. Loughran P. Beer-Stolz D. Billiar T.R. Esmon C.T. Tsung A. Histones activate the NLRP3 inflammasome in Kupffer cells during sterile inflammatory liver injury.J. Immunol. 2013; 191: 2665-2679Crossref PubMed Scopus (150) Google Scholar, 49Zhu P. Duan L. Chen J. Xiong A. Xu Q. Zhang H. Zheng F. Tan Z. Gong F. Fang M. 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NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder.Immunity. 2004; 20: 319-325Abstract Full Text Full Text PDF PubMed Scopus (1327) Google Scholar, 52Swanson K.V. Deng M. Ting J.P. The NLRP3 inflammasome: Molecular activation and regulation to therapeutics.Nat. Rev. Immunol. 2019; 19: 477-489Crossref PubMed Scopus (1262) Google Scholar). Next, we examined the UPR and inflammasome activation in KCs and hepatocytes that were freshly isolated from the livers of mice following I/R injury or sham control. Whereas more prominently increased IRE1α phosphorylation was detected in KCs than in hepatocytes from the livers after I/R injury, higher expression levels of XBP1s protein were seen
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