Acidic Microenvironment Regulates the Severity of Hepatic Ischemia/Reperfusion Injury by Modulating the Generation and Function of Tregs via the PI3K-mTOR Pathway
Acidic Microenvironment Regulates the Severity of Hepatic Ischemia/Reperfusion Injury by Modulating the Generation and Function of Tregs via the PI3K-mTOR Pathway
复制标题
酸性微环境通过 PI3K-mTOR 通路调节 Tregs 的生成和功能来调节肝缺血/再灌注损伤的严重程度
DOI：
10.3389/fimmu.2019.02945
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发表时间：
2020-01-09
影响因子：
7.3
通讯作者：
Lu, Ling
中科院分区：
文献类型：
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作者：
Gan, Xiaojie;Zhang, Rongsheng;Lu, Ling
肝缺血再灌注损伤(HIRI)是肝移植和肝切除术后肝功能障碍甚至肝功能衰竭的主要原因。导致HIRI的关键机制之一是酸性微环境，这种微环境是由于乳酸和酮体等高酸样物质的积累而形成的。先前的研究表明，诱导调节性T细胞(ITregs)的过继转移可以减轻HIRI；然而，对于Tregs在酸性微环境下HIRI模型中的作用，人们知之甚少。在本研究中，我们在体外和体内检测了酸性微环境对Tregs的影响。在这里，我们报道了人和小鼠在HIRI过程中诱导的微环境酸化和肝脏功能障碍，酸性微环境可以通过PI3K/Akt/mTOR信号通路抑制CD4(+)CD25(+)Foxp3(+)iTregs的生成和功能。相反，酸性微环境的逆转恢复了Foxp3的表达和iTreg功能。此外，体外细胞培养结果表明，质子泵抑制剂奥美拉唑改善了酸性微环境引起的iTreg分化减少，提示质子泵抑制剂有可能作为免疫调节疗法用于HIRI的治疗。此外，我们的发现表明缓冲酸性微环境以减轻小鼠的HIRI与Tregs有着密不可分的关系。因此，酸性微环境是HIRI的关键调节因子，参与调节Tregs的产生和功能。
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.