Frontiers in Immunology (Jan 2020)
Acidic Microenvironment Regulates the Severity of Hepatic Ischemia/Reperfusion Injury by Modulating the Generation and Function of Tregs via the PI3K-mTOR Pathway
- Xiaojie Gan,
- Xiaojie Gan,
- Xiaojie Gan,
- Xiaojie Gan,
- Rongsheng Zhang,
- Rongsheng Zhang,
- Rongsheng Zhang,
- Rongsheng Zhang,
- Jian Gu,
- Jian Gu,
- Jian Gu,
- Jian Gu,
- Zheng Ju,
- Zheng Ju,
- Zheng Ju,
- Zheng Ju,
- Xiao Wu,
- Xiao Wu,
- Xiao Wu,
- Xiao Wu,
- Qi Wang,
- Qi Wang,
- Qi Wang,
- Qi Wang,
- Hao Peng,
- Hao Peng,
- Hao Peng,
- Hao Peng,
- Jiannan Qiu,
- Jiannan Qiu,
- Jiannan Qiu,
- Jiannan Qiu,
- Jinren Zhou,
- Jinren Zhou,
- Jinren Zhou,
- Jinren Zhou,
- Feng Cheng,
- Feng Cheng,
- Feng Cheng,
- Feng Cheng,
- Ling Lu,
- Ling Lu,
- Ling Lu,
- Ling Lu
Affiliations
- Xiaojie Gan
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Xiaojie Gan
- Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- Xiaojie Gan
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
- Xiaojie Gan
- Key Laboratory of Living Donor Liver Transplantation, National Health Commission (NHC), Nanjing, China
- Rongsheng Zhang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Rongsheng Zhang
- Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- Rongsheng Zhang
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
- Rongsheng Zhang
- Key Laboratory of Living Donor Liver Transplantation, National Health Commission (NHC), Nanjing, China
- Jian Gu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Jian Gu
- Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- Jian Gu
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
- Jian Gu
- Key Laboratory of Living Donor Liver Transplantation, National Health Commission (NHC), Nanjing, China
- Zheng Ju
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Zheng Ju
- Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- Zheng Ju
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
- Zheng Ju
- Key Laboratory of Living Donor Liver Transplantation, National Health Commission (NHC), Nanjing, China
- Xiao Wu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Xiao Wu
- Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- Xiao Wu
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
- Xiao Wu
- Key Laboratory of Living Donor Liver Transplantation, National Health Commission (NHC), Nanjing, China
- Qi Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Qi Wang
- Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- Qi Wang
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
- Qi Wang
- Key Laboratory of Living Donor Liver Transplantation, National Health Commission (NHC), Nanjing, China
- Hao Peng
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Hao Peng
- Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- Hao Peng
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
- Hao Peng
- Key Laboratory of Living Donor Liver Transplantation, National Health Commission (NHC), Nanjing, China
- Jiannan Qiu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Jiannan Qiu
- Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- Jiannan Qiu
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
- Jiannan Qiu
- Key Laboratory of Living Donor Liver Transplantation, National Health Commission (NHC), Nanjing, China
- Jinren Zhou
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Jinren Zhou
- Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- Jinren Zhou
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
- Jinren Zhou
- Key Laboratory of Living Donor Liver Transplantation, National Health Commission (NHC), Nanjing, China
- Feng Cheng
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Feng Cheng
- Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- Feng Cheng
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
- Feng Cheng
- Key Laboratory of Living Donor Liver Transplantation, National Health Commission (NHC), Nanjing, China
- Ling Lu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Ling Lu
- Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- Ling Lu
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
- Ling Lu
- Key Laboratory of Living Donor Liver Transplantation, National Health Commission (NHC), Nanjing, China
- DOI
- https://doi.org/10.3389/fimmu.2019.02945
- Journal volume & issue
-
Vol. 10
Abstract
Hepatic ischemia/reperfusion injury (HIRI) is a major cause of liver dysfunction and even liver failure after liver transplantation and hepatectomy. One of the critical mechanisms that lead to HIRI is an acidic microenvironment, which develops due to the accumulation of high acid-like substances such as lactic acid and ketone bodies. Previous studies have shown that the adoptive transfer of induced regulatory T cells (iTregs) attenuates HIRI; however, little is known about the function of Tregs in the acidic microenvironment of a HIRI model. In the present study, we examined the effect of acidic microenvironment on Tregs in vitro and in vivo. Here, we report that microenvironment acidification and dysfunction of the liver is induced during HIRI in humans and mice and that an acidic microenvironment can inhibit the generation and function of CD4+CD25+Foxp3+ iTregs via the PI3K/Akt/mTOR signaling pathway. By contrast, the reversal of the acidic microenvironment restored Foxp3 expression and iTreg function. In addition, the results of cell culture in vitro indicated that the proton pump inhibitor omeprazole improves decreased iTreg differentiation caused by the acidic microenvironment, suggesting the potential clinical use of proton pump inhibitors as immunoregulatory therapy in the treatment of HIRI. Furthermore, our findings demonstrate that buffering the acidic microenvironment to attenuate HIRI in mice has an inseparable relationship with Tregs. Thus, an acidic microenvironment is a key regulator in HIRI, involved in modulating the generation and function of Tregs.
Keywords