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

Abstract

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 TNFα, 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. (Hepatology 2021;0:1-19).A cute-on-chronic liver failure (ACLF) is a complication of cirrhosis where patients progress through acute decompensation

Lipids in Liver Failure Syndromes: A Focus on Eicosanoids, Specialized Pro-Resolving Lipid Mediators and Lysophospholipids

“…Moreover, LPA induced the production of proinflammatory cytokines by CD14+ cells without increasing phagocytic capacity. Altogether these data suggest a pivotal role of the LPC-ATX-LPA axis in the immune dysfunction observed in ACLF that could be corrected through modulation of the axis ( 129 ) ( Figure 2 ). The evidence of lysophospholipids involvement in ACLF and their potential therapeutic implications have been summarized in Table 2 .…”

“…In ACLF, we recently reported that LPC-ATX-LPA axis modulates innate immunity (see below). Innate immunity is known to be associated with outcome in ALF ( 129 , 283 ), thus the study of LPC-ATX-LPA in this setting could be of great interest. Lysosphingolipids seem indeed related to multiple aspects of ALF and particularly hepatocyte death, mitochondrial and immune dysfunctions, however further studies are needed to elucidate the mechanisms involved.…”

“…Interestingly, ACLF patients who received albumin had increased levels of LPC after albumin therapy underlining the close relationship of LPC carriers and its circulating level ( 124 ). Serum of ACLF patients was depleted in LPCs with up-regulation of LPA levels ( 129 ), with higher ACLF grades associated with lowest LPC concentrations. The latter also correlated with an anti-inflammatory monocyte profile, with high Mer-tyrosine-kinase (MerTK) and CD163 expressions and low HLA-DR expression.…”

Inhibition of Autotaxin and Lysophosphatidic Acid Receptor 5 Attenuates Neuroinflammation in LPS-Activated BV-2 Microglia and a Mouse Endotoxemia Model

“…In the LPS-induced acute lung injury mouse model, on the other hand, genetic or pharmacologic targeting of ATX had only minor effects on disease severity [42]. In contrast, there is evidence that a dysregulated ATX/LPA axis (decreased LPC, increased ATX expression and LPA concentration) in acute-on chronic liver failure (ACLF) associates with mortality and systemic infection [43]. The same group reported that LPS stimulates ATX gene expression and increases the inflammatory phenotype of monocytes that are isolated from ACLF patients [43].…”

“…In contrast, there is evidence that a dysregulated ATX/LPA axis (decreased LPC, increased ATX expression and LPA concentration) in acute-on chronic liver failure (ACLF) associates with mortality and systemic infection [43]. The same group reported that LPS stimulates ATX gene expression and increases the inflammatory phenotype of monocytes that are isolated from ACLF patients [43]. In line with this, it was demonstrated that LPS induces a massive increase in ATX mRNA and protein expression via autocrine IFN-γ signaling in monocytic THP-1 cells [44].…”