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

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...

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Autores principales:	Alexander A. Maini, Natalia Becares, Louise China, Thais H. Tittanegro, Amit Patel, Roel P.H. De Maeyer, Nekisa Zakeri, Tu Vinh Long, Lucy Ly, Derek W. Gilroy, Alastair O’Brien
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	HLA-DR TNF IL6 LPS Cyclo-oxygenase 1 Microsomal PGE synthase 1 Diseases of the digestive system. Gastroenterology RC799-869
Acceso en línea:	https://doaj.org/article/d3345bc59a7b459581475c760ed2675d
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spelling	oai:doaj.org-article:d3345bc59a7b459581475c760ed2675d2021-11-20T05:11:29ZMonocyte dysfunction in decompensated cirrhosis is mediated by the prostaglandin E2-EP4 pathway2589-555910.1016/j.jhepr.2021.100332https://doaj.org/article/d3345bc59a7b459581475c760ed2675d2021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2589555921001087https://doaj.org/toc/2589-5559Background & 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.Alexander A. MainiNatalia BecaresLouise ChinaThais H. TittanegroAmit PatelRoel P.H. De MaeyerNekisa ZakeriTu Vinh LongLucy LyDerek W. GilroyAlastair O’BrienElsevierarticleHLA-DRTNFIL6LPSCyclo-oxygenase 1Microsomal PGE synthase 1Diseases of the digestive system. GastroenterologyRC799-869ENJHEP Reports, Vol 3, Iss 6, Pp 100332- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	HLA-DR TNF IL6 LPS Cyclo-oxygenase 1 Microsomal PGE synthase 1 Diseases of the digestive system. Gastroenterology RC799-869
spellingShingle	HLA-DR TNF IL6 LPS Cyclo-oxygenase 1 Microsomal PGE synthase 1 Diseases of the digestive system. Gastroenterology RC799-869 Alexander A. Maini Natalia Becares Louise China Thais H. Tittanegro Amit Patel Roel P.H. De Maeyer Nekisa Zakeri Tu Vinh Long Lucy Ly Derek W. Gilroy Alastair O’Brien Monocyte dysfunction in decompensated cirrhosis is mediated by the prostaglandin E2-EP4 pathway
description	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.
format	article
author	Alexander A. Maini Natalia Becares Louise China Thais H. Tittanegro Amit Patel Roel P.H. De Maeyer Nekisa Zakeri Tu Vinh Long Lucy Ly Derek W. Gilroy Alastair O’Brien
author_facet	Alexander A. Maini Natalia Becares Louise China Thais H. Tittanegro Amit Patel Roel P.H. De Maeyer Nekisa Zakeri Tu Vinh Long Lucy Ly Derek W. Gilroy Alastair O’Brien
author_sort	Alexander A. Maini
title	Monocyte dysfunction in decompensated cirrhosis is mediated by the prostaglandin E2-EP4 pathway
title_short	Monocyte dysfunction in decompensated cirrhosis is mediated by the prostaglandin E2-EP4 pathway
title_full	Monocyte dysfunction in decompensated cirrhosis is mediated by the prostaglandin E2-EP4 pathway
title_fullStr	Monocyte dysfunction in decompensated cirrhosis is mediated by the prostaglandin E2-EP4 pathway
title_full_unstemmed	Monocyte dysfunction in decompensated cirrhosis is mediated by the prostaglandin E2-EP4 pathway
title_sort	monocyte dysfunction in decompensated cirrhosis is mediated by the prostaglandin e2-ep4 pathway
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/d3345bc59a7b459581475c760ed2675d
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Monocyte dysfunction in decompensated cirrhosis is mediated by the prostaglandin E2-EP4 pathway

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