Enhanced lactate accumulation upregulates PD-L1 expression to delay neutrophil apoptosis in sepsis

IF 9.7 4区 医学 Q1 MATERIALS SCIENCE, BIOMATERIALS VIEW Pub Date : 2023-12-20 DOI:10.1002/viw.20230053
Miaomiao Fei, Hui Zhang, Fanbing Meng, Guanghui An, Jinxuan Tang, Jianbin Tong, Lize Xiong, Qidong Liu, Cheng Li
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Abstract

Malfunction of neutrophil apoptosis and elevated serum lactate levels are the key cellular mechanism of immune suppressive status in septic patients. However, whether increased lactate affects apoptosis of neutrophils and aggravates sepsis development, and the molecular mechanism remain unknown. In this study, first, we analyzed the transcriptional profiles of blood cells in sepsis patients (n = 39) and healthy volunteers (n = 40) to reveal that there is close correlation between the lactate-related gene expression changes associated with lactate production and immune function in leukocytes, especially in neutrophils. Further, we explored the close relationship between lactate and delayed neutrophil apoptosis in human neutrophils. Programmed cell death 1 legand (PD-L1) was highly expressed in septic patients compared with healthy volunteers. Then, we indicated that elevated levels of lactate in human neutrophils decreased neutrophil apoptosis (P < .001) by upregulating PD-L1 expression. Inhibition of monocarboxylate transporter 1 (MCT1) significantly attenuated neutrophil apoptosis caused by lactate (P < .001). We further performed in vivo experiments in sepsis mice model and determined that increased lactate decreased neutrophil apoptosis (P < .05) and reduces mice survival rate (P < .001), which could also be rescued by MCT1 inhibitor (P < .05). This study revealed that elevated level of lactate in sepsis upregulates PD-L1 expression to decrease apoptosis through MCT1 in neutrophils, which provides new insight into sepsis treatment strategy by reducing lactate accumulation.

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乳酸积累的增强可上调 PD-L1 的表达,从而延缓败血症中中性粒细胞的凋亡
中性粒细胞凋亡功能障碍和血清乳酸水平升高是脓毒症患者免疫抑制状态的关键细胞机制。然而,乳酸增高是否会影响中性粒细胞的凋亡并加重脓毒症的发展,其分子机制仍不清楚。在本研究中,我们首先分析了脓毒症患者(39 人)和健康志愿者(40 人)血液细胞的转录谱,发现乳酸相关基因表达的变化与白细胞尤其是中性粒细胞的免疫功能密切相关。此外,我们还探讨了乳酸盐与人类中性粒细胞延迟凋亡之间的密切关系。与健康志愿者相比,脓毒症患者体内的程序性细胞死亡 1 legand(PD-L1)表达量较高。随后,我们发现人类中性粒细胞中乳酸水平的升高会通过上调 PD-L1 的表达来减少中性粒细胞的凋亡(P <.001)。抑制单羧酸盐转运体 1(MCT1)可显著减轻乳酸盐引起的中性粒细胞凋亡(P < .001)。我们进一步在脓毒症小鼠模型中进行了体内实验,结果发现乳酸增加会减少中性粒细胞的凋亡(P < .05)并降低小鼠的存活率(P < .001),而 MCT1 抑制剂也能挽救这种情况(P < .05)。这项研究揭示了脓毒症中乳酸水平升高会上调PD-L1的表达,从而通过MCT1减少中性粒细胞的凋亡,这为通过减少乳酸积累来治疗脓毒症提供了新的思路。
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来源期刊
VIEW
VIEW Multiple-
CiteScore
12.60
自引率
2.30%
发文量
0
审稿时长
10 weeks
期刊介绍: View publishes scientific articles studying novel crucial contributions in the areas of Biomaterials and General Chemistry. View features original academic papers which go through peer review by experts in the given subject area.View encourages submissions from the research community where the priority will be on the originality and the practical impact of the reported research.
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