Dysregulated anti-oxidant signalling and compromised mitochondrial integrity negatively influence regulatory T cell function and viability in liver disease.
Dysregulated anti-oxidant signalling and compromised mitochondrial integrity negatively influence regulatory T cell function and viability in liver disease.
复制标题
抗氧化信号失调和线粒体完整性受损会对肝脏疾病中的调节性T细胞功能和活力产生负面影响。
DOI：
10.1016/j.ebiom.2023.104778
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发表时间：
2023-09
期刊：
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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作者：
炎症反应失调和氧化应激是慢性炎症性疾病如肝硬化（LC）的关键致病驱动因素。调节性T细胞（TCRs）对于防止过度免疫激活和维持组织稳态至关重要。虽然众所周知炎症因子调节TclO的功能和稳定性，但TclO受氧化应激影响的程度尚未完全研究。将从LC患者分离的CD 4 + CD 25 + CD 127 lo/-T细胞的表型和功能特性与健康对照（HC）进行比较。通过表征细胞内活性氧（ROS）、NADPH氧化酶-2（Nox 2）活性、线粒体功能、形态和核因子-红细胞2相关因子（Nrf 2）抗氧化信号传导来研究Treg氧化还原状态。使用小鼠模型和CRISPR/Cas9介导的HO-1敲除进一步评估了Nrf 2及其下游靶标血红素加氧酶-1（HO-1）在Treg功能、稳定性和存活中的相关性。来自LC患者的循环TlR显示抑制功能降低，与肝病严重程度相关，与表型异常和细胞凋亡增加相关。从机制上讲，这与Nrf 2信号转导失调有关，导致HO-1水平降低，Nox 2活化增强，线粒体呼吸和完整性受损。在LC Tcirrhosis的功能缺陷可以部分重演培养控制Tcirrhosis患者血清。我们的研究结果表明，TdR依赖于功能性氧化还原稳态的功能，稳定性和生存。靶向Treg特异性抗氧化途径可能具有逆转氧化损伤状况（如晚期肝病）中的Treg损伤的治疗潜力。本研究由（211113/A/18/Z）资助。
Dysregulated inflammatory responses and oxidative stress are key pathogenic drivers of chronic inflammatory diseases such as liver cirrhosis (LC). Regulatory T cells (Tregs) are essential to prevent excessive immune activation and maintain tissue homeostasis. While inflammatory cues are well known to modulate the function and stability of Tregs, the extent to which Tregs are influenced by oxidative stress has not been fully explored. The phenotypic and functional properties of CD4+CD25+CD127lo/- Tregs isolated from patients with LC were compared to healthy controls (HC). Treg redox state was investigated by characterizing intracellular reactive oxygen species (ROS), NADPH oxidase-2 (Nox2) activity, mitochondrial function, morphology, and nuclear factor-erythroid 2-related factor (Nrf2) antioxidant signalling. The relevance of Nrf2 and its downstream target, Heme-oxygenase-1 (HO-1), in Treg function, stability, and survival, was further assessed using mouse models and CRISPR/Cas9-mediated HO-1 knock-out. Circulating Tregs from LC patients displayed a reduced suppressive function, correlating with liver disease severity, associated with phenotypic abnormalities and increased apoptosis. Mechanistically, this was linked to a dysregulated Nrf2 signalling with resultant lower levels of HO-1, enhanced Nox2 activation, and impaired mitochondrial respiration and integrity. The functional deficit in LC Tregs could be partially recapitulated by culturing control Tregs in patient sera. Our findings reveal that Tregs rely on functional redox homeostasis for their function, stability, and survival. Targeting Treg specific anti-oxidant pathways may have therapeutic potential to reverse the Treg impairment in conditions of oxidative damage such as advanced liver disease. This study was funded by the (211113/A/18/Z).
影响因子：
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作者：
Rotblat B;Grunewald TG;Leprivier G;Melino G;Knight RA
通讯作者：
Knight RA