The linoleic acid-derived leukotoxin 9,10-DiHOME drives immunosuppression in patients with acute-on-chronic liver failure

BACKGROUND AIMS: Patients with acutely decompensated cirrhosis (ADC) present severe immune dysfunction characterized by smoldering systemic inflammation and persistent immunosuppression rendering them at increased risk of bacterial infections and acute-on-chronic liver failure (ACLF). APPROACH RESULTS: We explored the profile of 98 immunomodulatory lipid mediators in ADC patients with and without ACLF and their effects on leukocyte function. We performed LC-MS/MS-based lipidomics of 308 plasma samples longitudinally collected from 93 ADC patients with and without ACLF and integrated expression and flow cytometry data with functional assays in leukocytes. Lipidomics identified the linoleic acid-derived leukotoxin 9,10-dihydroxy-12-octadecenoic acid (9,10-DiHOME) as the only lipid mediator elevated in ACLF. 9,10-DiHOME levels followed the disease severity course and peaked when patients acquired infections and developed ACLF. Leukocytes from ADC patients showed increased expression of soluble epoxide hydrolase (sEH), the enzyme responsible for 9,10-DiHOME biosynthesis. In polymorphonuclear leukocytes, 9,10-DiHOME impaired degranulation, phagocytosis, and respiratory burst capacities. In mononuclear leukocytes, this lipid mediator induced the expression of the immunosuppressive marker MerTK, impaired their ability to produce cytokines in response to LPS and disrupted mitochondrial dynamics and autophagic responses. Inhibition of sEH in vivo reduced immunosuppressive responses in peritoneal macrophages and significantly attenuated MerTK expression in liver macrophages. CONCLUSIONS: These findings indicate that increased levels of the leukotoxin 9,10-DiHOME weakens immune-cell defensive responses and position sEH as a potential drug target in ADC.