肾上腺髓质素作为肝衰竭综合征中CD14+MerTK+循环单核细胞的免疫调节剂。

IF 4.2 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY
Francesca Maria Trovato, Florent Artru, Roosey Sheth, Rima Abdalla, Joseph Wilson, Anna Broderick, John Smith, Stephen Atkinson, Mark J McPhail
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引用次数: 0

摘要

背景和目的:肝衰竭综合征的特征是免疫反应失调导致免疫瘫痪。肾上腺髓质素(ADM)是一种有效的血管舒张剂和免疫调节剂。本研究旨在探讨ADM在肝功能衰竭中的作用,并假设ADM与肾上腺髓质素结合蛋白(AMBP)1之间存在有害的失衡,从而促进单核细胞/巨噬细胞向促恢复表型和功能的转变。方法:纳入2020年4月至2024年6月期间连续出现急性肝衰竭(ALF)、急性伴慢性肝衰竭(ACLF)和失代偿性肝硬化的患者以及健康对照组(HC)。分离外周血单核细胞/单核细胞,用于RNA测序和细胞培养。采用酶联免疫吸附法检测ADM和AMBP1。结果:纳入54例ALF患者,25例ACLF患者,9例失代偿性肝硬化患者,16例HC患者。与HC相比,ALF (log fold change = 5.88, p = 0.000216413)和ACLF (log fold change = 4.62, p = 0.00057122)分离的单核细胞中ADM表达增加。ALF组血浆ADM浓度(1684±1156 pg/mL)高于ACLF组(836.1±765.2 pg/mL)和HC组(164.8±62.73 pg/mL)。与ACLF(126.3±72.23µg/mL)和HC(252.8±159.7µg/mL)相比,ALF(59.27±44µg/mL)的AMBP1显著降低(p < 0.0001)。LPS处理使外周血单核细胞上清ADM浓度升高(ALF n = 6; 561.4±1038 pg/mL vs. 259.2±213.7 pg/mL; ACLF n = 4; 3202±491.2 vs. 1757±1689 pg/mL)。LPS培养后表达Mer酪氨酸激酶的CD14+细胞比例降低(2.077±0.87%);与ADM 100 nM共培养,表型恢复(3.852±1.063%)。结论:肝功能衰竭时ADM升高,而AMBP1降低。ADM影响单核细胞功能,增加Mer酪氨酸激酶,促进促恢复,抗炎表型。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Adrenomedullin as an Immunomodulator of CD14+MerTK+ Circulating Monocytes in Liver Failure Syndromes.

Background and aims: Liver failure syndromes are characterised by a dysregulated immune response leading to immune paralysis. Adrenomedullin (ADM) is a potent vasodilator and immunoregulator. This study aimed to explore the role of ADM in liver failure, hypothesising that there is a detrimental imbalance between ADM and adrenomedullin binding protein (AMBP)1 that promotes a switch of monocytes/macrophages towards a pro-restorative phenotype and function.

Methods: Consecutive patients with acute liver failure (ALF), acute-on-chronic liver failure (ACLF), and decompensated cirrhosis, as well as healthy controls (HC) were included between April 2020 and June 2024. Peripheral blood mononuclear cells/monocytes were isolated and used for RNA sequencing and cell culture. ADM and AMBP1 were measured by enzyme-linked immunosorbent assay.

Results: Fifty-four patients with ALF, 25 with ACLF, 9 with decompensated cirrhosis, and 16 with HC were included. ADM expression in isolated monocytes was increased in ALF (log fold change = 5.88, p = 0.000216413) and ACLF (log fold change = 4.62, p = 0.00057122) compared to HC. Plasma ADM concentration was higher in ALF (1,684 ± 1,156 pg/mL) vs. ACLF (836.1 ± 765.2 pg/mL) and HC (164.8 ± 62.73 pg/mL). AMBP1 was significantly reduced in ALF (59.27 ± 44 µg/mL) vs. ACLF (126.3 ± 72.23 µg/mL) and HC (252.8 ± 159.7 µg/mL) (p < 0.0001, ALF vs. HC). Treatment with LPS increased ADM concentration in peripheral blood mononuclear cell supernatant (ALF n = 6; 561.4 ± 1,038 pg/mL vs. 259.2 ± 213.7 pg/mL, ACLF n = 4; 3,202 ± 491.2 vs. 1,757 ± 1,689 pg/mL). The percentage of CD14+ cells expressing Mer tyrosine kinase was reduced after culture with LPS (2.077 ± 0.87%); however, co-culture with ADM 100 nM restored the phenotype (3.852 ± 1.063%).

Conclusions: ADM is increased in liver failure, whereas AMBP1 is reduced. ADM affects monocyte function, increasing Mer Tyrosine Kinase and promoting a pro-restorative, anti-inflammatory phenotype.

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来源期刊
Journal of Clinical and Translational Hepatology
Journal of Clinical and Translational Hepatology GASTROENTEROLOGY & HEPATOLOGY-
CiteScore
6.40
自引率
2.80%
发文量
496
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