Peritoneal Level of CD206 Associates With Mortality and an Inflammatory Macrophage Phenotype in Patients With Decompensated Cirrhosis and Spontaneous Bacterial Peritonitis
2020
Abstract Background & Aims Peritoneal macrophages (PM) regulate inflammation and control bacterial infections in patients with decompensated cirrhosis. We aimed to characterize PM and associate their activation with outcomes of patients with spontaneous bacterial peritonitis (SBP). Methods We isolated PM from ascites samples of 67 patients with decompensated cirrhosis (20 with SBP) and analyzed them by flow cytometry, quantitative real-time PCR, 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 (TNF) by ELISA (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 PM (LPM) and small PM (SPM), which differed in granularity and maturation markers, in ascites samples from patients with cirrhosis. LPM vs SPM from patients with cirrhosis had different transcriptomes; we identified more than 4000 genes that were differentially regulated in LPM vs SPM, including those that regulate the cycle, metabolism, self-renewal, and immune cell signaling. LPM had an inflammatory phenotype, were less susceptible to tolerance induction, and released more TNF than SPM. LPM from patients with cirrhosis produced more inflammatory cytokines than LPM from controls. Activation of PM by toll-like receptor agonists and live bacteria altered levels of CD206 on the surface of LPM and release of soluble CD206. Analysis of serial ascites fluid from patients with SBP revealed loss of LPM 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 (above 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 PM in patients with cirrhosis. Soluble CD206 is released from activated LPM, and increased concentrations in patients with cirrhosis and SBP indicate reduced odds of surviving for 90 days.
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