Monocyte dysfunction in decompensated cirrhosis is mediated by the prostaglandin E2-EP4 pathway
| العنوان: | Monocyte dysfunction in decompensated cirrhosis is mediated by the prostaglandin E2-EP4 pathway |
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| المؤلفون: | Louise China, Nekisa Zakeri, Tu Vinh Long, Alexander A. Maini, Amit Patel, Thais Helena Tittanegro, Alastair O'Brien, Roel P.H. De Maeyer, Natalia Becares, Derek W. Gilroy, Lucy Ly |
| المصدر: | JHEP Reports, Vol 3, Iss 6, Pp 100332-(2021) JHEP Reports |
| بيانات النشر: | Elsevier BV, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Cirrhosis, TNF, Decompensated cirrhosis, RC799-869, cPGES, cytosolic PGE synthase, HPGD, 15-hydroxyprostaglandin dehydrogenase, Gastroenterology, Liver disease, MDMs, monocyte-derived macrophages, Microsomal PGE synthase 1, Ascites, LC-MS/MS, liquid chromatography-tandem mass spectrometry, CM, classical monocytes, Immunology and Allergy, MFI, mean fluorescence intensity, TNFα, tumour necrosis factor alpha, Whole blood, TIPS, transjugular intrahepatic portosystemic shunt insertion, EIA, enzyme immune assay, HLA DR, human leukocyte antigen – DR isotype, Diseases of the digestive system. Gastroenterology, Jaundice, sCD14, soluble CD14, medicine.anatomical_structure, CRP, C-reactive protein, LPS, lipopolysaccharide, lipids (amino acids, peptides, and proteins), medicine.symptom, Research Article, HVs, healthy volunteers, medicine.medical_specialty, LPS, CAID, cirrhosis-associated immune dysfunction, NASH, non-alcoholic steatohepatitis, mPGES1, microsomal PGE synthase 1, Cyclo-oxygenase 1, White blood cell, Internal medicine, PGE2, prostaglandin E2, Internal Medicine, medicine, Decompensation, FACS, polychromatic flow cytometric analysis, Hepatology, business.industry, Monocyte, HLA-DR, OPD, patients with refractory ascites attending hospital outpatient department for day case paracentesis, DSS, downstream synthases, medicine.disease, AD, acute decompensation, IL6, COX, cyclooxygenase, ACLF, acute-on-chronic liver failure, qPCR, quantitative PCR, business |
| الوصف: | 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. Graphical abstract Highlights • We demonstrate that monocyte dysfunction in patients with decompensated cirrhosis and refractory ascites is mediated by PGE2 through its EP4 receptor. • Monocyte HLA-DR expression was also reduced in both cohorts of patients with decompensated cirrhosis, at least in part, by elevated circulating PGE2. • Up to 55% of patients with ACLF have an infective precipitant. • Improving monocyte function in patients with pre-hospital cirrhosis and ascites could prevent development of ACLF. • PGE2-EP4 receptor antagonists might represent a treatment to improve monocyte dysfunction in outpatients with ascites. |
| تدمد: | 2589-5559 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3389d2aeb9a6d0bb948f1425e23e31fcTest https://doi.org/10.1016/j.jhepr.2021.100332Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....3389d2aeb9a6d0bb948f1425e23e31fc |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 25895559 |
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