The following is a summary of the “Lysophosphatidylcholines modulate immunoregulatory checkpoints in peripheral monocytes and are associated with mortality in people with acute liver failure,” published in the March 2023 issue of Hepatology by Trovato, et al.
High mortality from sepsis is linked to the life-threatening condition known as acute liver failure (ALF), characterized by high levels of inflammation and impaired immunity. Here, we set out to characterize the metabolic dysregulation seen in ALF and to ascertain whether or not systemic immunological responses are regulated by the lysophosphatidylcholine (LPC)-autotaxin (ATX)-lysophosphatidic acid (LPA) pathway. Recruitment included 96 patients with ALF, 104 with cirrhosis, 31 with sepsis, and 71 HCs. Multivariate statistical analysis of proton nuclear magnetic resonance spectroscopy and untargeted ultraperformance liquid chromatography-mass spectrometry-based lipidomics led to discovery of pathways of interest.
Validation was performed using a specific metabolomics panel. Flow cytometry was used to measure the surface expression of immunological checkpoint molecules after peripheral blood mononuclear cells were grown with LPA 16:0, 18:0, and 18:1. In this study, they analyzed the effect of LPAR antagonism in vitro and looked at how LPAR is expressed at the transcript level in monocytes. The discriminatory power of LPC 16:0 between ALF and HC was excellent. Those with ALF had higher levels of ATX and LPA than healthy controls and those with sepsis. Those with ALF had lower levels of the LPCs 16:0, 18:0, and 18:1, all associated with a bad prognosis.
LPA 16:0 treatment of monocytes resulted in upregulation of PD-L1 expression and downregulation of CD155, CD163, and MerTK levels but did not affect T or NK/CD56+T cell immunological checkpoints. In vitro, antagonism of LPAR1 and 3 prevented LPA from downregulating MerTK and CD163 expression in monocytes. The expression of MerTK and CD163 was elevated in monocytes from people with ALF relative to controls, whereas LPAR genes were not. Patients with ALF whose LPC levels are low have a dismal prognosis. LPAR1 and LPAR3 may regulate the innate immune response in ALF via the LPC-ATX-LPA axis. Further research is needed to locate therapeutic drugs that specifically target these receptors.