Hyperglycemia Aggravates Hepatic Ischemia and Reperfusion Injury by Inhibiting Liver-Resident Macrophage M2 Polarization via C/EBP Homologous Protein-Mediated Endoplasmic Reticulum Stress
Aggravated liver ischemia and reperfusion (IR) injury has been observed in hyperglycemic hosts, but its underlying mechanism remains undefined. Liver-resident macrophages (Kupffer cells, KCs) and endoplasmic reticulum (ER) stress play crucial roles in the pathogenesis of liver IR injury. In this stu...
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| Format: | Article |
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Frontiers Media S.A.
2017-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2017.01299/full |
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| author | Zhuqing Rao Jie Sun Xiongxiong Pan Ziyang Chen Heliang Sun Panpan Zhang Mei Gao Zhengnian Ding Cunming Liu |
| author_facet | Zhuqing Rao Jie Sun Xiongxiong Pan Ziyang Chen Heliang Sun Panpan Zhang Mei Gao Zhengnian Ding Cunming Liu |
| author_sort | Zhuqing Rao |
| collection | DOAJ |
| description | Aggravated liver ischemia and reperfusion (IR) injury has been observed in hyperglycemic hosts, but its underlying mechanism remains undefined. Liver-resident macrophages (Kupffer cells, KCs) and endoplasmic reticulum (ER) stress play crucial roles in the pathogenesis of liver IR injury. In this study, we evaluated the role of ER stress in regulating KC activation and liver IR injury in a streptozotocin-induced hyperglycemic/diabetic mouse model. Compared to the control group (CON group), hyperglycemic mice exhibited a significant increase in liver injury and intrahepatic inflammation following IR. KCs obtained from hyperglycemic mice secreted higher levels of the pro-inflammatory factors TNF-α and IL-6, while they secreted significantly lower levels of the anti-inflammatory factor IL-10. Furthermore, enhanced ER stress was revealed by increased C/EBP homologous protein (CHOP) activation in both IR-stressed livers and KCs from hyperglycemic mice. Specific CHOP knockdown in KCs by siRNA resulted in a slight decrease in TNF-α and IL-6 secretion but dramatically enhanced anti-inflammatory IL-10 secretion in the hyperglycemic group, while no significant changes in cytokine production were observed in the CON group. We also analyzed the role of hyperglycemia in macrophage M1/M2 polarization. Interestingly, we found that hyperglycemia inhibited IL-10-secreting M2-like macrophage polarization, as revealed by decreased Arg1 and Mrc1 gene induction accompanied by a decrease in STAT3 and STAT6 signaling pathway activation. CHOP knockdown restored Arg1 and Mrc1 gene induction, STAT3 and STAT6 activation, and most importantly, IL-10 secretion in hyperglycemic KCs. Finally, in vivo CHOP knockdown in KCs enhanced intrahepatic anti-inflammatory IL-10 gene induction and protected the liver against IR injury in hyperglycemic mice but had no significant effects in control mice. Our results demonstrate that hyperglycemia induces hyper-inflammatory activation of KCs during liver IR injury. Thus, hyperglycemia-induced CHOP over-activation inhibits IL-10-secreting M2-like macrophage polarization by liver-resident macrophages, thereby leading to excessive inflammation and the exacerbation of liver IR injury in diabetic/hyperglycemic hosts. This study provides novel mechanistic insight into macrophage inflammatory activation under hyperglycemic conditions during liver IR. |
| first_indexed | 2024-12-20T21:38:57Z |
| format | Article |
| id | doaj.art-1c60dbbeef324dc49440ac8cc691ef98 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-20T21:38:57Z |
| publishDate | 2017-10-01 |
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| series | Frontiers in Immunology |
| spelling | doaj.art-1c60dbbeef324dc49440ac8cc691ef982022-12-21T19:25:52ZengFrontiers Media S.A.Frontiers in Immunology1664-32242017-10-01810.3389/fimmu.2017.01299305367Hyperglycemia Aggravates Hepatic Ischemia and Reperfusion Injury by Inhibiting Liver-Resident Macrophage M2 Polarization via C/EBP Homologous Protein-Mediated Endoplasmic Reticulum StressZhuqing Rao0Jie Sun1Xiongxiong Pan2Ziyang Chen3Heliang Sun4Panpan Zhang5Mei Gao6Zhengnian Ding7Cunming Liu8Department of Anesthesiology, First Affiliated Hospital with Nanjing Medical University, Nanjing, ChinaDepartment of Anesthesiology, First Affiliated Hospital with Nanjing Medical University, Nanjing, ChinaDepartment of Anesthesiology, First Affiliated Hospital with Nanjing Medical University, Nanjing, ChinaDepartment of Anesthesiology, First Affiliated Hospital with Nanjing Medical University, Nanjing, ChinaDepartment of Anesthesiology, First Affiliated Hospital with Nanjing Medical University, Nanjing, ChinaDepartment of Anesthesiology, First Affiliated Hospital with Nanjing Medical University, Nanjing, ChinaDepartment of Anesthesiology, First Affiliated Hospital with Nanjing Medical University, Nanjing, ChinaDepartment of Anesthesiology, First Affiliated Hospital with Nanjing Medical University, Nanjing, ChinaDepartment of Anesthesiology, First Affiliated Hospital with Nanjing Medical University, Nanjing, ChinaAggravated liver ischemia and reperfusion (IR) injury has been observed in hyperglycemic hosts, but its underlying mechanism remains undefined. Liver-resident macrophages (Kupffer cells, KCs) and endoplasmic reticulum (ER) stress play crucial roles in the pathogenesis of liver IR injury. In this study, we evaluated the role of ER stress in regulating KC activation and liver IR injury in a streptozotocin-induced hyperglycemic/diabetic mouse model. Compared to the control group (CON group), hyperglycemic mice exhibited a significant increase in liver injury and intrahepatic inflammation following IR. KCs obtained from hyperglycemic mice secreted higher levels of the pro-inflammatory factors TNF-α and IL-6, while they secreted significantly lower levels of the anti-inflammatory factor IL-10. Furthermore, enhanced ER stress was revealed by increased C/EBP homologous protein (CHOP) activation in both IR-stressed livers and KCs from hyperglycemic mice. Specific CHOP knockdown in KCs by siRNA resulted in a slight decrease in TNF-α and IL-6 secretion but dramatically enhanced anti-inflammatory IL-10 secretion in the hyperglycemic group, while no significant changes in cytokine production were observed in the CON group. We also analyzed the role of hyperglycemia in macrophage M1/M2 polarization. Interestingly, we found that hyperglycemia inhibited IL-10-secreting M2-like macrophage polarization, as revealed by decreased Arg1 and Mrc1 gene induction accompanied by a decrease in STAT3 and STAT6 signaling pathway activation. CHOP knockdown restored Arg1 and Mrc1 gene induction, STAT3 and STAT6 activation, and most importantly, IL-10 secretion in hyperglycemic KCs. Finally, in vivo CHOP knockdown in KCs enhanced intrahepatic anti-inflammatory IL-10 gene induction and protected the liver against IR injury in hyperglycemic mice but had no significant effects in control mice. Our results demonstrate that hyperglycemia induces hyper-inflammatory activation of KCs during liver IR injury. Thus, hyperglycemia-induced CHOP over-activation inhibits IL-10-secreting M2-like macrophage polarization by liver-resident macrophages, thereby leading to excessive inflammation and the exacerbation of liver IR injury in diabetic/hyperglycemic hosts. This study provides novel mechanistic insight into macrophage inflammatory activation under hyperglycemic conditions during liver IR.http://journal.frontiersin.org/article/10.3389/fimmu.2017.01299/fullliver ischemia and reperfusionhyperglycemiamacrophageKupffer cellendoplasmic reticulum stressC/EBP homologous protein |
| spellingShingle | Zhuqing Rao Jie Sun Xiongxiong Pan Ziyang Chen Heliang Sun Panpan Zhang Mei Gao Zhengnian Ding Cunming Liu Hyperglycemia Aggravates Hepatic Ischemia and Reperfusion Injury by Inhibiting Liver-Resident Macrophage M2 Polarization via C/EBP Homologous Protein-Mediated Endoplasmic Reticulum Stress Frontiers in Immunology liver ischemia and reperfusion hyperglycemia macrophage Kupffer cell endoplasmic reticulum stress C/EBP homologous protein |
| title | Hyperglycemia Aggravates Hepatic Ischemia and Reperfusion Injury by Inhibiting Liver-Resident Macrophage M2 Polarization via C/EBP Homologous Protein-Mediated Endoplasmic Reticulum Stress |
| title_full | Hyperglycemia Aggravates Hepatic Ischemia and Reperfusion Injury by Inhibiting Liver-Resident Macrophage M2 Polarization via C/EBP Homologous Protein-Mediated Endoplasmic Reticulum Stress |
| title_fullStr | Hyperglycemia Aggravates Hepatic Ischemia and Reperfusion Injury by Inhibiting Liver-Resident Macrophage M2 Polarization via C/EBP Homologous Protein-Mediated Endoplasmic Reticulum Stress |
| title_full_unstemmed | Hyperglycemia Aggravates Hepatic Ischemia and Reperfusion Injury by Inhibiting Liver-Resident Macrophage M2 Polarization via C/EBP Homologous Protein-Mediated Endoplasmic Reticulum Stress |
| title_short | Hyperglycemia Aggravates Hepatic Ischemia and Reperfusion Injury by Inhibiting Liver-Resident Macrophage M2 Polarization via C/EBP Homologous Protein-Mediated Endoplasmic Reticulum Stress |
| title_sort | hyperglycemia aggravates hepatic ischemia and reperfusion injury by inhibiting liver resident macrophage m2 polarization via c ebp homologous protein mediated endoplasmic reticulum stress |
| topic | liver ischemia and reperfusion hyperglycemia macrophage Kupffer cell endoplasmic reticulum stress C/EBP homologous protein |
| url | http://journal.frontiersin.org/article/10.3389/fimmu.2017.01299/full |
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