Sven Stengel1, Stefanie Quickert1, Philipp Lutz2, Oluwatomi Ibidapo-Obe1, Arndt Steube1, Nilay Köse-Vogel1, Melina Yarbakht3, Philipp A Reuken1, Martin Busch4, Annette Brandt5, Ina Bergheim5, Sachin D Deshmukh6, Andreas Stallmach1, Tony Bruns7. 1. Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany. 2. Department of Internal Medicine I, University of Bonn, Bonn, Germany; German Center for Infection Research, University of Bonn, Bonn, Germany. 3. Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany; The Integrated Research and Treatment Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany. 4. Department of Internal Medicine III, Jena University Hospital, Jena, Germany. 5. Department of Nutritional Sciences, R.F. Molecular Nutritional Science, University of Vienna, Vienna, Austria. 6. The Integrated Research and Treatment Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany. 7. Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena, Germany; The Integrated Research and Treatment Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany; Department of Internal Medicine III, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany. Electronic address: tbruns@ukaachen.de.
Abstract
BACKGROUND & AIMS: Peritoneal macrophages (PMs) regulate inflammation and control bacterial infections in patients with decompensated cirrhosis. We aimed to characterize PMs and associate their activation with outcomes of patients with spontaneous bacterial peritonitis (SBP). METHODS: We isolated PMs from ascites samples of 67 patients with decompensated cirrhosis (20 with SBP) and analyzed them by flow cytometry, quantitative real-time polymerase chain reaction, functional analysis, and RNA microarrays. We used ascites samples of a separate cohort of 120 patients with decompensated cirrhosis (76 with SPB) and quantified the soluble form of the mannose receptor (CD206) and tumor necrosis factor by enzyme-linked immunosorbent assay (test cohort). We performed logistic regression analysis to identify factors associated with 90-day mortality. We validated our findings using data from 71 patients with cirrhosis and SBP. Data from 14 patients undergoing peritoneal dialysis for end-stage renal disease but without cirrhosis were included as controls. RESULTS: We used surface levels of CD206 to identify subsets of large PMs (LPM) and small PMs (SPM), which differed in granularity and maturation markers, in ascites samples from patients with cirrhosis. LPMs vs SPMs from patients with cirrhosis had different transcriptomes; we identified more than 4000 genes that were differentially regulated in LPMs vs SPMs, including those that regulate the cycle, metabolism, self-renewal, and immune cell signaling. LPMs had an inflammatory phenotype, were less susceptible to tolerance induction, and released more tumor necrosis factor than SPMs. LPMs from patients with cirrhosis produced more inflammatory cytokines than LPMs from controls. Activation of PMs by Toll-like receptor agonists and live bacteria altered levels of CD206 on the surface of LPMs and release of soluble CD206. Analysis of serial ascites fluid from patients with SBP revealed loss of LPMs in the early phase of SBP, but levels increased after treatment. In the test and validation cohorts, patients with SBP and higher concentrations of soluble CD206 in ascites fluid (>0.53 mg/L) were less likely to survive for 90 days than those with lower levels. CONCLUSIONS: Surface level of CD206 can be used to identify mature, resident, inflammatory PMs in patients with cirrhosis. Soluble CD206 is released from activated LPMs and increased concentrations in patients with cirrhosis and SBP indicate reduced odds of surviving for 90 days.
BACKGROUND & AIMS: Peritoneal macrophages (PMs) regulate inflammation and control bacterial infections in patients with decompensated cirrhosis. We aimed to characterize PMs and associate their activation with outcomes of patients with spontaneous bacterial peritonitis (SBP). METHODS: We isolated PMs from ascites samples of 67 patients with decompensated cirrhosis (20 with SBP) and analyzed them by flow cytometry, quantitative real-time polymerase chain reaction, functional analysis, and RNA microarrays. We used ascites samples of a separate cohort of 120 patients with decompensated cirrhosis (76 with SPB) and quantified the soluble form of the mannose receptor (CD206) and tumor necrosis factor by enzyme-linked immunosorbent assay (test cohort). We performed logistic regression analysis to identify factors associated with 90-day mortality. We validated our findings using data from 71 patients with cirrhosis and SBP. Data from 14 patients undergoing peritoneal dialysis for end-stage renal disease but without cirrhosis were included as controls. RESULTS: We used surface levels of CD206 to identify subsets of large PMs (LPM) and small PMs (SPM), which differed in granularity and maturation markers, in ascites samples from patients with cirrhosis. LPMs vs SPMs from patients with cirrhosis had different transcriptomes; we identified more than 4000 genes that were differentially regulated in LPMs vs SPMs, including those that regulate the cycle, metabolism, self-renewal, and immune cell signaling. LPMs had an inflammatory phenotype, were less susceptible to tolerance induction, and released more tumor necrosis factor than SPMs. LPMs from patients with cirrhosis produced more inflammatory cytokines than LPMs from controls. Activation of PMs by Toll-like receptor agonists and live bacteria altered levels of CD206 on the surface of LPMs and release of soluble CD206. Analysis of serial ascites fluid from patients with SBP revealed loss of LPMs in the early phase of SBP, but levels increased after treatment. In the test and validation cohorts, patients with SBP and higher concentrations of soluble CD206 in ascites fluid (>0.53 mg/L) were less likely to survive for 90 days than those with lower levels. CONCLUSIONS: Surface level of CD206 can be used to identify mature, resident, inflammatory PMs in patients with cirrhosis. Soluble CD206 is released from activated LPMs and increased concentrations in patients with cirrhosis and SBP indicate reduced odds of surviving for 90 days.
Authors: Philipp A Reuken; Jonathan F Brozat; Alexander Koch; Tony Bruns; Stefanie Quickert; Oluwatomi Ibidapo-Obe; Johanna Reißing; Anika Franz; Sven Stengel; Ulf K-M Teichgräber; Michael Kiehntopf; Christian Trautwein; Andreas Stallmach Journal: J Intensive Care Date: 2022-06-11
Authors: Johanna Reißing; Philipp Lutz; Mick Frissen; Oluwatomi Ibidapo-Obe; Philipp A Reuken; Theresa H Wirtz; Sven Stengel; Stefanie Quickert; Michael Rooney; Karsten Große; Henning W Zimmermann; Christian Trautwein; Andreas Stallmach; Tony Bruns Journal: JHEP Rep Date: 2021-11-03
Authors: Vanessa Marchant; Antonio Tejera-Muñoz; Laura Marquez-Expósito; Sandra Rayego-Mateos; Raul R Rodrigues-Diez; Lucia Tejedor; Laura Santos-Sanchez; Jesús Egido; Alberto Ortiz; Jose M Valdivielso; Donald J Fraser; Manuel López-Cabrera; Rafael Selgas; Marta Ruiz-Ortega Journal: Biomolecules Date: 2020-09-24