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"Chronic liver disease gets worse when the liver's immune system stays overactive, resulting in ongoing inflammation and scarring. Signals from the gut make the situation worse by encouraging immune cells to release harmful molecules. Macrophages and monocytes are central players, intensifying injury and shifting the body's defenses toward a more aggressive state. Among them, liver macrophages are essential and are now being explored as therapeutic targets. ..."
From the highlights and abstract:
"Highlights
• PAF/PAF-R signaling pathway is overactivated in patients with cirrhosis.
• PAF/PAF-R blockade ameliorates liver injury during experimental cirrhosis.
• Antagonizing PAF/PAF-R pathway restores homeostatic Treg/Th17 immune balance.
• Promoter DNA methylation controls PAF-R expression in hepatic macrohages.
Abstract
Background and aims
Platelet-activating factor (PAF) phospholipid is mainly produced by macrophages and involved in pro-inflammatory responses. We evaluated the regulation of PAF-R gene expression during experimental cirrhosis and whether antagonizing its ligand PAF improves liver function and inflammation.
Methods
Patients with cirrhosis and CCl4-induced cirrhotic C57Bl/6 mice were included in the study. A subgroup of mice was treated with either PAF antagonist BN-52021 or a DNMT inhibitor, Aza, for two weeks before laparotomies. Sorted hepatic macrophages were subjected to a genome-wide DNA methylation study, and Ptafr expression analysed by Western Blot, qPCR, and immunohistochemistry in liver tissue. Immortalized Kupffer cells (imKCs) were stimulated with PAF and antigenic ligands. Cytokine and chemokine expression were measured. Biochemical and hepatic markers of liver damage were assessed.
Results
Hepatic PAF-R increased in patients and the CCl4 cirrhotic model. PAF antagonism reduced hepatic structural damage and improved endothelial function in cirrhotic mice.
Also in vivo, PAF-R signalling pathway inhibition rebalanced hepatic cytokine response modifying the Th17-Treg axis in experimental cirrhosis. PAF-R was induced by CpG and TNF-α in vitro, and the PAF-R/PAF pathway stimulation elicited proinflammatory cytokine production in imKCs. PAF-R expression was controlled by Ptafr promoter CpGs demethylation in hepatic macrophages from cirrhotic mice. This mechanism was confirmed by targeting enzymes inhibiting DNMTs in charge of DNA-methylation with Aza in imKCs.
Conclusion
PAF antagonist BN-52021 disrupts PAF-R/PAF signaling counteracting PAF-R overexpression, and ameliorates liver injury in cirrhotic mice. Ptafr expression is controlled by promoter DNA demethylation leading to PAFR overexpression in hepatic macrophages."
Blocking a key inflammatory pathway improves liver structure and vascular function in cirrhosis, study finds "A preclinical study identifies a key inflammatory mechanism driving liver injury and shows it could be targeted to develop new treatments for cirrhosis, a disease responsible for over one million deaths worldwide each year"
Graphical abstract
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