Acidic Microenvironment Regulates the Severity of Hepatic Ischemia/Reperfusion Injury by Modulating the Generation and Function of Tregs via the PI3K-mTOR Pathway

Gan, Xiaojie; Zhang, Rongsheng; Gu, Jian; Zheng, Jie; Wu, Xiao; Wang, Qi; Peng, Hao; Qiu, Jiannan; Zhou, Jiang; Cheng, Feng; Lü, Ling

doi:10.3389/fimmu.2019.02945

Cited by 25 publications

(19 citation statements)

References 40 publications

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“…The most prominent feature of Treg cells is the expression of Foxp3 and the demethylation of the Foxp3 gene locus (Hoeppli et al, 2015). In recent years, experiments have confirmed that by regulating Th17/Treg cell balance, the severity of renal IRI could be alleviated (Gan et al, 2019). Cleophas et al (2016)…”

Section: Discussionmentioning

confidence: 99%

Butyric Acid Protects Against Renal Ischemia–Reperfusion Injury by Adjusting the Treg/Th17 Balance via HO-1/p-STAT3 Signaling

Chen

Wang

Yang

et al. 2021

Front. Cell Dev. Biol.

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Immune regulation plays a vital role in ischemia–reperfusion injury (IRI). Butyric acid (BA) has immunomodulatory effects in many diseases, but its immunomodulatory effects during renal IRI are still unclear. Our research shows that BA protected against IRI and significantly improved renal IRI in vivo. In vitro studies showed that BA inhibits Th17 cell differentiation and induces Treg cell differentiation. Mechanism studies have shown that heme oxygenase 1 (HO-1)/STAT3 signaling pathway was involved in the inhibitory effect of BA on Th17 cell differentiation. HO-1 inhibitors can significantly rescue the BA-mediated inhibition of Th17 cell differentiation. We confirmed that BA promotes the differentiation of Th17 cells into Treg cells by regulating the pathway and reduces renal IRI.

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Section: Discussionmentioning

confidence: 99%

Butyric Acid Protects Against Renal Ischemia–Reperfusion Injury by Adjusting the Treg/Th17 Balance via HO-1/p-STAT3 Signaling

Chen

Wang

Yang

et al. 2021

Front. Cell Dev. Biol.

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“…On the other hand, interaction with BSA prior to injection might inhibit such an increase after intravenous injection, subsequently more penetration might occur. In CCl 4 -induced hepatitis condition, extracellular pH in the liver might decrease, as is similar with the case of acute liver ischemia/reperfusion injury [50]. Under the decreased pH condition, zeta potential of the lipoplex increased ( Table 2).…”

Section: Discussionmentioning

confidence: 57%

Interaction of Lipoplex with Albumin Enhances Gene Expression in Hepatitis Mice

et al. 2020

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Understanding the in vivo fate of lipoplex, which is composed of cationic liposomes and DNA, is an important issue toward gene therapy. In disease conditions, the fate of lipoplex might change compared with the normal condition. Here, we examined the contribution of interaction with serum components to in vivo transfection using lipoplex in hepatitis mice. Prior to administration, lipoplex was incubated with serum or albumin. In the liver, the interaction with albumin enhanced gene expression in hepatitis mice, while in the lung, the interaction with serum or albumin enhanced it. In normal mice, the interaction with albumin did not enhance hepatic and pulmonary gene expression. Furthermore, hepatic and pulmonary gene expression levels of albumin-interacted lipoplex were correlated with serum transaminases in hepatitis mice. The albumin interaction increased the hepatic accumulation of lipoplex and serum tumor necrosis factor-α level. We suggest that the interaction with albumin enhanced the inflammation level after the administration of lipoplex in hepatitis mice. Consequently, the enhancement of the inflammation level might enhance the gene expression level. Information obtained in the current study will be valuable toward future clinical application of the lipoplex.

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“…For instance, while the lower PH promotes the expression of nitric oxide synthase in macrophages ( 22 ) and the activity of neutrophils ( 23 ), it also inhibits cytotoxic natural killer cells ( 24 ). Recently, Gan proved that acidic microenvironment decreased Tregs and increased the severity of HIRI ( 11 ). Therefore, the extracellular acidic microenvironment may have different effects on macrophages.…”

Section: Discussionmentioning

confidence: 99%

“…Under ischemia conditions, the promotion of anaerobic glycolysis and accumulation of lactic acid may cause the generation of acidic microenvironment while the pH values of blood or tissues go down to the PH of 6.0 to 6.5. A recent study showed that such a change in the microenvironment may suppress the generation of T regulatory cells (Tregs) and cause an immune imbalance which aggravated HIRI ( 10 ). Therefore, the acidic microenvironment is one of most important factors leading to HIRI.…”

Section: Introductionmentioning

confidence: 99%

Acidic Microenvironment Aggravates the Severity of Hepatic Ischemia/Reperfusion Injury by Modulating M1-Polarization Through Regulating PPAR-γ Signal

Ding

Duan

et al. 2021

Front. Immunol.

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Hepatic injury induced by ischemia and reperfusion (HIRI) is a major clinical problem after liver resection or transplantation. The polarization of macrophages plays an important role in regulating the severity of hepatic ischemia/reperfusion injury. Recent evidence had indicated that the ischemia induces an acidic microenvironment by causing increased anaerobic glycolysis and accumulation of lactic acid. We hypothesize that the acidic microenvironment might cause the imbalance of intrahepatic immunity which aggravated HIRI. The hepatic ischemia/reperfusion injury model was established to investigate the effect of the acidic microenvironment to liver injury. Liposomes were used to deplete macrophages in vivo. Macrophages were cultured under low pH conditions to analyze the polarization of macrophages in vitro. Activation of the PPAR-γ signal was determined by Western blot. PPAR-γ agonist GW1929 was administrated to functionally test the role of PPAR-γ in regulating macrophage-mediated effects in the acidic microenvironment during HIRI. We demonstrate that acidic microenvironment aggravated HIRI while NaHCO3 reduced liver injury through neutralizing the acid, besides, liposome abolished the protective ability of NaHCO3 through depleting the macrophages. In vivo and vitro experiment showed that acidic microenvironment markedly promoted M1 polarization but inhibited M2 polarization of macrophage. Furthermore, the mechanistic study proved that the PPAR-γ signal was suppressed during the polarization of macrophages under pH = 6.5 culture media. The addition of PPAR-γ agonist GW1929 inhibited M1 polarization under acidic environment and reduced HIRI. Our results indicate that acidic microenvironment is a key regulator in HIRI which promoted M1 polarization of macrophages through regulating PPAR-γ. Conversely, PPAR-γ activation reduced liver injury, which provides a novel therapeutic concept to prevent HIRI.

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Acidic Microenvironment Regulates the Severity of Hepatic Ischemia/Reperfusion Injury by Modulating the Generation and Function of Tregs via the PI3K-mTOR Pathway

Cited by 25 publications

References 40 publications

Butyric Acid Protects Against Renal Ischemia–Reperfusion Injury by Adjusting the Treg/Th17 Balance via HO-1/p-STAT3 Signaling

Butyric Acid Protects Against Renal Ischemia–Reperfusion Injury by Adjusting the Treg/Th17 Balance via HO-1/p-STAT3 Signaling

Interaction of Lipoplex with Albumin Enhances Gene Expression in Hepatitis Mice

Acidic Microenvironment Aggravates the Severity of Hepatic Ischemia/Reperfusion Injury by Modulating M1-Polarization Through Regulating PPAR-γ Signal

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