TY - JOUR
T1 - Dysregulation of the Lysophosphatidylcholine/Autotaxin/Lysophosphatidic Acid Axis in Acute-on-Chronic Liver Failure Is Associated With Mortality and Systemic Inflammation by Lysophosphatidic Acid–Dependent Monocyte Activation
AU - Trovato, Francesca M.
AU - Zia, Rabiya
AU - Napoli, Salvatore
AU - Wolfer, Kate
AU - Huang, Xiaohong
AU - Morgan, Phillip E.
AU - Husbyn, Hannah
AU - Elgosbi, Marwa
AU - Lucangeli, Manuele
AU - Miquel, Rosa
AU - Wilson, Ian
AU - Heaton, Nigel David
AU - Heneghan, Michael A.
AU - Auzinger, Georg
AU - Antoniades, Charalambos G.
AU - Wendon, Julia A.
AU - Patel, Vishal C.
AU - Coen, Muireann
AU - Triantafyllou, Evangelos
AU - McPhail, Mark J.
N1 - Funding Information:
This article is dedicated to the memory of Dr. Charalambous “Harry” Antoniades who sadly died during the preparation of this work. M.J.W.M. is grateful to the Biomedical Research Council at Guys and St Thomas NHS Foundation Trust, Kings Health Partners, and Kings College Hospital Charity for infrastructure, salary, and consumables support. J.W., V.C.P., and M.M. are grateful to the Intensive Society UK for support. M.M., M.C., I.W., and R.Z. are grateful to the Medical Research Council for support, and E.T. and C.G.A. are grateful to Imperial College for fellowship support for E.T.
Funding Information:
This article is dedicated to the memory of Dr. Charalambous ?Harry? Antoniades who sadly died during the preparation of this work. M.J.W.M. is grateful to the Biomedical Research Council at Guys and St Thomas NHS Foundation Trust, Kings Health Partners, and Kings College Hospital Charity for infrastructure, salary, and consumables support. J.W., V.C.P., and M.M. are grateful to the Intensive Society UK for support. M.M., M.C., I.W., and R.Z. are grateful to the Medical Research Council for support, and E.T. and C.G.A. are grateful to Imperial College for fellowship support for E.T.
Publisher Copyright:
© 2021 by the American Association for the Study of Liver Diseases.
PY - 2021/8
Y1 - 2021/8
N2 - Background & Aims: Acute-on-chronic liver failure (ACLF) is characterized by systemic inflammation, monocyte dysfunction, and susceptibility to infection. Lysophosphatidylcholines (LPCs) are immune-active lipids whose metabolic regulation and effect on monocyte function in ACLF is open for study. Approaches & Results: Three hundred forty-two subjects were recruited and characterized for blood lipid, cytokines, phospholipase (PLA), and autotaxin (ATX) concentration. Peripheral blood mononuclear cells and CD14
+ monocytes were cultured with LPC, or its autotaxin (ATX)-derived product, lysophosphatidic acid (LPA), with or without lipopolysaccharide stimulation and assessed for surface marker phenotype, cytokines production, ATX and LPA-receptor expression, and phagocytosis. Hepatic ATX expression was determined by immunohistochemistry. Healthy volunteers and patients with sepsis or acute liver failure served as controls. ACLF serum was depleted in LPCs with up-regulated LPA levels. Patients who died had lower LPC levels than survivors (area under the receiver operating characteristic curve, 0.94; P < 0.001). Patients with high-grade ACLF had the lowest LPC concentrations and these rose over the first 3 days of admission. ATX concentrations were higher in patients with AD and ACLF and correlated with Model for End-Stage Liver Disease, Consortium on Chronic Liver Failure–Sequential Organ Failure Assessment, and LPC/LPA concentrations. Reduction in LPC correlated with higher monocyte Mer-tyrosine-kinase (MerTK) and CD163 expression. Plasma ATX concentrations rose dynamically during ACLF evolution, correlating with IL-6 and TNF-α, and were associated with increased hepatocyte ATX expression. ACLF patients had lower human leukocyte antigen-DR isotype and higher CD163/MerTK monocyte expression than controls; both CD163/MerTK expression levels were reduced in ACLF ex vivo following LPA, but not LPC, treatment. LPA induced up-regulation of proinflammatory cytokines by CD14
+ cells without increasing phagocytic capacity. Conclusions: ATX up-regulation in ACLF promotes LPA production from LPC. LPA suppresses MerTK/CD163 expression and increases monocyte proinflammatory cytokine production. This metabolic pathway could be investigated to therapeutically reprogram monocytes in ACLF.
AB - Background & Aims: Acute-on-chronic liver failure (ACLF) is characterized by systemic inflammation, monocyte dysfunction, and susceptibility to infection. Lysophosphatidylcholines (LPCs) are immune-active lipids whose metabolic regulation and effect on monocyte function in ACLF is open for study. Approaches & Results: Three hundred forty-two subjects were recruited and characterized for blood lipid, cytokines, phospholipase (PLA), and autotaxin (ATX) concentration. Peripheral blood mononuclear cells and CD14
+ monocytes were cultured with LPC, or its autotaxin (ATX)-derived product, lysophosphatidic acid (LPA), with or without lipopolysaccharide stimulation and assessed for surface marker phenotype, cytokines production, ATX and LPA-receptor expression, and phagocytosis. Hepatic ATX expression was determined by immunohistochemistry. Healthy volunteers and patients with sepsis or acute liver failure served as controls. ACLF serum was depleted in LPCs with up-regulated LPA levels. Patients who died had lower LPC levels than survivors (area under the receiver operating characteristic curve, 0.94; P < 0.001). Patients with high-grade ACLF had the lowest LPC concentrations and these rose over the first 3 days of admission. ATX concentrations were higher in patients with AD and ACLF and correlated with Model for End-Stage Liver Disease, Consortium on Chronic Liver Failure–Sequential Organ Failure Assessment, and LPC/LPA concentrations. Reduction in LPC correlated with higher monocyte Mer-tyrosine-kinase (MerTK) and CD163 expression. Plasma ATX concentrations rose dynamically during ACLF evolution, correlating with IL-6 and TNF-α, and were associated with increased hepatocyte ATX expression. ACLF patients had lower human leukocyte antigen-DR isotype and higher CD163/MerTK monocyte expression than controls; both CD163/MerTK expression levels were reduced in ACLF ex vivo following LPA, but not LPC, treatment. LPA induced up-regulation of proinflammatory cytokines by CD14
+ cells without increasing phagocytic capacity. Conclusions: ATX up-regulation in ACLF promotes LPA production from LPC. LPA suppresses MerTK/CD163 expression and increases monocyte proinflammatory cytokine production. This metabolic pathway could be investigated to therapeutically reprogram monocytes in ACLF.
UR - http://www.scopus.com/inward/record.url?scp=85107884540&partnerID=8YFLogxK
U2 - 10.1002/hep.31738
DO - 10.1002/hep.31738
M3 - Article
C2 - 33908067
SN - 0270-9139
VL - 74
SP - 907
EP - 925
JO - Hepatology
JF - Hepatology
IS - 2
ER -