Linking platelet lipidome and inflammatory response in septic patients

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Sepsis is characterized by major endothelial dysfunction, microvascular alterations, and coagulopathy. Platelets are important players in sepsis as they promote thrombo-inflammation and generate lipidic mediators of inflammation. Previously, we observed that platelet acetyl-CoA carboxylase 1 (ACC1), responsible for de novo lipid synthesis, is phosphorylated and thus inhibited by AMP-activated protein kinase (AMPK) upon thrombin stimulation, leading to platelet lipidome changes. The role of the AMPK-ACC signaling in the regulation of platelet lipidome during sepsis, and its potential impact on inflammation, has never been investigated. To investigate whether changes in ACC phosphorylation can influence the platelet lipidome and the inflammatory response of patients during sepsis. Platelets and plasmas were isolated from 48 septic and 48 control patients. In parallel, WT and DKI mice injected intraperitoneally with lipopolysaccharides were used as a model of endotoxemia. Platelets ACC1 phosphorylation/expression levels were measured by western blot. Lipidomics analysis was carried out by untargeted liquid chromatography–mass spectrometry or on the commercial Lipidyzer platform. Plasma factors were measured by Enzyme-linked immunosorbent assays (ELISA). Platelet ACC1 expression and phosphorylation were increased both in septic patients and in septic mice. Lipidomics analysis highlighted significant changes of lipids in human and murine platelets during sepsis, with a substantial reduction in phosphatidylcholines and phosphatidylethanolamines containing long polyunsaturated fatty acid chains (ω3 and ω6), which are key phospholipids for the generation of pro- and anti-inflammatory lipid mediators. Our preliminary data obtained in humans and mice, suggest that elevated ACC phosphorylation in sepsis is associated with a higher content of these phospholipids as well as a plasma reduction in myeloid inflammatory parameters. Our data reveal that critical changes in the platelet lipidome occur during sepsis and may contribute to the pathophysiology of the disease. Our results also suggest that ACC can influence the platelet lipid content and/or composition.