Immunomodulatory receptor VSIG4 is released during spontaneous bacterial peritonitis and predicts short-term mortality

Abstract

Background & Aims 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, VSIG4 hi 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. Lay summary 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.

Transcriptomics unveils immune metabolic disruption and a novel biomarker of mortality in patients with HBV-related acute-on-chronic liver failure

“… 41 Higher peritoneal VSIG4 levels can be used to predict the prognosis of spontaneous bacterial peritonitis, while regulating the ratio of VSIG4-expressing macrophage subpopulations might provide new therapies for cirrhosis and ascites. 42 , 43 Our results showed that the VSIG4 expression level was significantly correlated with T-cell activation/differentiation and inflammatory response-related bioprocesses and positively associated with WBC, INR and neutrophil levels in patients with HBV-ACLF, which is consistent with the findings of previous studies, indicating that the potential function of VSIG4 may be to correct immune disorders during ACLF progression. VSIG4 is tightly linked with serum urea levels, which might alleviate acute kidney injury by suppressing inflammation.…”

Peritoneal Immunity in Liver Disease

“…Interestingly, peritoneal macrophages shed VSIG4 during SBP, and the level of soluble VSIG4 in ascites is correlated with disease severity and mortality from SBP. However, soluble VSIG4 does not directly affect peritoneal macrophage lipopolysaccharide (LPS)-induced TNF-α release or phagocytic activity [26]. Other groups have found that during SBP episodes, LPMs change to a more inflammatory phenotype characterised by low CD206, low MER Proto-Oncogne Tyrosine Kinase (MERTK) and normal CD163 cell surface expression.…”