Dynamic changes in macrophage populations in MASLD and its influence on prostaglandin E2-mediated signaling

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is rising rapidly. In the severe form of steatohepatitis (MASH) steatosis is accompanied by an infiltration of immune cells, inflammatory processes and beginning fibrosis, which increases the risk of developing hepatocellular carcinoma. Kupffer cells, resident liver macrophages, represent the largest pool of macrophages in the organism and, in parallel with other inflammatory mediators, primarily produce the prostanoid prostaglandin E2 (PGE2), which acts mainly in a paracrine and autocrine manner. During MASLD progression to MASH the hepatic macrophage pool changes and this could influence PGE2-mediated signaling processes. The aim of the study was to characterize the macrophage pool in MASH and its sensitivity to PGE2.

Flow cytometry analysis of mice liver identified three macrophage pools in animals fed with a MASH-inducing diet compared to one pool in animals fed a standard diet. The number of Kupffer cells decreases over time and were replaced by monocyte-derived cells with a Kupffer cell similar phenotype. The largest increase was quantified from monocyte-derived macrophages with a clear pro-inflammatory phenotype, which infiltrate the liver. Parallel in-vitro studies with primary isolated Kupffer cells and potential infiltration macrophages sources from wildtype and cyclooxygenase 2-deficient mice were performed to investigate the role of PGE2. Compared to Kupffer cells, monocyte-derived macrophages produce less PGE2 but react much more sensitive to this prostanoid, which could inhibit the basal and lipopolysaccharide-mediated expression of TNFalpha and other pro-inflammatory signaling mediators. In conclusion, differences in PGE2-sensitivity in macrophages may influence inflammatory processes in MASH progression.

Publication History

Article published online:
20 January 2025