Monocyte dysfunction in decompensated cirrhosis is mediated by the prostaglandin E2-EP4 pathway

Abstract

Background & aims: Infection is a major problem in advanced liver disease secondary to monocyte dysfunction. Elevated prostaglandin (PG)E₂ is a mediator of monocyte dysfunction in cirrhosis; thus, we examined PGE₂ signalling in outpatients with ascites and in patients hospitalised with acute decompensation to identify potential therapeutic targets aimed at improving monocyte dysfunction.

Methods: Using samples from 11 outpatients with ascites and 28 patients hospitalised with decompensated cirrhosis, we assayed plasma levels of PGE₂ and lipopolysaccharide (LPS); performed quantitative real-time PCR on monocytes; and examined peripheral blood monocyte function. We performed western blotting and immunohistochemistry for PG biosynthetic machinery expression in liver tissue. Finally, we investigated the effect of PGE₂ antagonists in whole blood using polychromatic flow cytometry and cytokine production.

Results: We show that hepatic production of PGE₂ via the cyclo-oxygenase 1-microsomal PGE synthase 1 pathway, and circulating monocytes contributes to increased plasma PGE₂ in decompensated cirrhosis. Transjugular intrahepatic sampling did not reveal whether hepatic or monocytic production was larger. Blood monocyte numbers increased, whereas individual monocyte function decreased as patients progressed from outpatients with ascites to patients hospitalised with acute decompensation, as assessed by Human Leukocyte Antigen (HLA)-DR isotype expression and tumour necrosis factor alpha and IL6 production. PGE₂ mediated this dysfunction via its EP₄ receptor.

Conclusions: PGE₂ mediates monocyte dysfunction in decompensated cirrhosis via its EP₄ receptor and dysfunction was worse in hospitalised patients compared with outpatients with ascites. Our study identifies a potential drug target and therapeutic opportunity in these outpatients with ascites to reverse this process to prevent infection and hospital admission.

Lay summary: Patients with decompensated cirrhosis (jaundice, fluid build-up, confusion, and vomiting blood) have high infection rates that lead to high mortality rates. A white blood cell subset, monocytes, function poorly in these patients, which is a key factor underlying their sensitivity to infection. We show that monocyte dysfunction in decompensated cirrhosis is mediated by a lipid hormone in the blood, prostaglandin E₂, which is present at elevated levels, via its EP₄ pathway. This dysfunction worsens when patients are hospitalised with complications of cirrhosis compared with those in the outpatients setting, which supports the EP₄ pathway as a potential therapeutic target for patients to prevent infection and hospitalisation.

Keywords: ACLF, acute-on-chronic liver failure; AD, acute decompensation; CAID, cirrhosis-associated immune dysfunction; CM, classical monocytes; COX, cyclooxygenase; CRP, C-reactive protein; Cyclo-oxygenase 1; DSS, downstream synthases; Decompensated cirrhosis; EIA, enzyme immune assay; FACS, polychromatic flow cytometric analysis; HLA DR, human leukocyte antigen – DR isotype; HLA-DR; HPGD, 15-hydroxyprostaglandin dehydrogenase; HVs, healthy volunteers; IL6; LC-MS/MS, liquid chromatography-tandem mass spectrometry; LPS; LPS, lipopolysaccharide; MDMs, monocyte-derived macrophages; MFI, mean fluorescence intensity; Microsomal PGE synthase 1; NASH, non-alcoholic steatohepatitis; OPD, patients with refractory ascites attending hospital outpatient department for day case paracentesis; PGE2, prostaglandin E2; TIPS, transjugular intrahepatic portosystemic shunt insertion; TNF; TNFα, tumour necrosis factor alpha; cPGES, cytosolic PGE synthase; mPGES1, microsomal PGE synthase 1; qPCR, quantitative PCR; sCD14, soluble CD14.