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

ABSTRACT Background & Aims V-set immunoglobulin-domain-containing 4 (VSIG4) is an immuno-modulatory macrophage complement receptor modulating innate and adaptive immunity and affecting the resolution of bacterial infections. Given its expression on peritoneal macrophages (PM), we hypothesized a prognostic role of peritoneal VSIG4 concentrations in patients with spontaneous bacterial peritonitis (SBP). Methods We isolated PM from patients with cirrhosis and analyzed VSIG4 expression and release by flow cytometry, quantitative real-time PCR, 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 ascitic soluble VSIG4 with 90-days survival after SBP using Kaplan-Meier statistics, Cox regression, and competing-risks regression analysis. Results VSIG4 expression was high on resting, large peritoneal macrophages, which co-expressed CD206, CD163, and MERTK. VSIG4 gene expression in PM decreased in patients with SBP and normalized after resolution. During SBP, VSIG4hi PM were depleted (25% vs. 57%; P Conclusions VSIG4 is released from activated PM 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.