目的:含Ig结构域的V-set4(VSIG4)是一种免疫调节性巨噬细胞补体受体,可调节先天和适应性免疫,并影响细菌感染的解决。鉴于其在腹膜巨噬细胞(PMs)上的表达,我们假设腹膜VSIG4浓度在自发性细菌性腹膜炎(SBP)患者中的预后作用.
方法:我们从肝硬化患者中分离PMs,并通过流式细胞术分析VSIG4表达和释放,实时定量PCR,ELISA,和共聚焦显微镜。我们测量了120例SBP患者和40例无SBP患者的腹水中可溶性VSIG4浓度,并使用Kaplan-Meier统计方法研究了腹水中可溶性VSIG4与SBP后90天生存率的关系。Cox回归,和竞争风险回归分析。
结果:静息时VSIG4表达高,大型PM,共表达CD206,CD163和酪氨酸蛋白激酶Mer(MERTK)。SBP患者PMs中VSIG4基因表达降低,消退后恢复正常。在SBP期间,VSIG4hiPM耗尽(25%与57%;p<0.001),腹水中的可溶性VSIG4在SBP患者中高于无SBP患者(0.73vs.0.35μg/ml;p<0.0001)。通过Toll样受体(TLR)激动剂或体外活细菌感染的PM活化导致表面VSIG4的丧失和可溶性VSIG4的释放。机械上,PM中VSIG4的脱落是蛋白酶依赖性的,并且容易受到微管运输抑制。腹水中可溶性VSIG4超过血清浓度,并与血清肌酐相关,SBP期间终末期肝病评分和C反应蛋白的模型。1.0206μg/ml或更高的浓度表明90天死亡率增加(风险比1.70;95%CI1.01-2.86;p=0.046)。
结论:在SBP期间,VSIG4从活化的PMs释放到腹水中。较高的腹膜VSIG4水平表明患者具有器官衰竭和不良预后。
背景:发生腹水的肝硬化患者感染和死亡的风险增加。我们的研究表明,在感染腹水的患者中,补体受体VSIG4由常驻巨噬细胞释放到可以测量的腹液中。腹水中这种蛋白质水平升高的患者在90天内死亡的风险很高。
OBJECTIVE: V-set Ig-domain-containing 4 (VSIG4) is an immunomodulatory macrophage complement receptor modulating innate and adaptive immunity and affecting the resolution of bacterial infections. Given its expression on peritoneal macrophages (PMs), we hypothesised a prognostic role of peritoneal VSIG4 concentrations in patients with spontaneous bacterial peritonitis (SBP).
METHODS: We isolated PMs from patients with cirrhosis and analysed VSIG4 expression and release by flow cytometry, quantitative real-time PCR, ELISA, and confocal microscopy. We measured soluble VSIG4 concentrations in ascites from 120 patients with SBP and 40 patients without SBP and investigated the association of soluble VSIG4 in ascites with 90-day survival after SBP using Kaplan-Meier statistics, Cox regression, and competing-risks regression analysis.
RESULTS: VSIG4 expression was high on resting, large PMs, which co-expressed CD206, CD163, and tyrosine-protein kinase Mer (MERTK). VSIG4 gene expression in PMs decreased in patients with SBP and normalised after resolution. During SBP, VSIG4hi PMs were depleted (25% vs. 57%; p <0.001) and soluble VSIG4 in ascites were higher in patients with SBP than in patients without (0.73 vs. 0.35 μg/ml; p <0.0001). PM activation by Toll-like receptor (TLR) agonists or infection with live bacteria in vitro resulted in a loss of surface VSIG4 and the release of soluble VSIG4. Mechanistically, shedding of VSIG4 from PMs was protease-dependent and susceptible to microtubule transport inhibition. Soluble VSIG4 in ascites exceeded serum concentrations and correlated with serum creatinine, model for end-stage liver disease score and C-reactive protein during SBP. Concentrations of 1.0206 μg/ml or higher indicated increased 90-day mortality (hazard ratio 1.70; 95% CI 1.01-2.86; p = 0.046).
CONCLUSIONS: VSIG4 is released from activated PMs into ascites during SBP. Higher peritoneal VSIG4 levels indicate patients with organ failure and poor prognosis.
BACKGROUND: Patients with liver cirrhosis who develop ascites have an increased risk of infection and mortality. Our study shows that in patients with infected ascites, the complement receptor VSIG4 is released by resident macrophages into the abdominal fluid where it can be measured. Patients with elevated levels of this protein in ascites are at high risk of dying within 90 days.