Adenosine A2AR agonist blocks mesenteric lymphatic epithelium, adipose tissue and Treg cells links of metabolic dysfunction-associated steatotic liver disease mice

Abstract

Recent studies in diet-induced obese mice indicate crosstalk among mesentery, spleen, serum, and liver metabolites. Observations include decreased expression of the adenosine A2A receptor (A2AR), mesenteric lymphatic hyperpermeability, and reduced Treg cell populations in splenic and adipose tissues in metabolic dysfunction-associated steatotic liver disease (MASLD). This study aims to investigate the mechanisms and effects of a four-week treatment with the A2AR agonist CGS21680 in mice on a high-fat, high-sucrose diet-induced MASLD. In MASLD mice, reduced levels of mesenteric A2AR and the lymphatic epithelial marker LYVE1 (lymphatic vessel endothelial hyaluronan receptor 1) are associated with decreased Treg and M2 phenotype markers, alongside increased permeability markers/permeability of mesenteric lymphatic epithelium. Furthermore, elevated levels of pro-inflammatory cytokines IL-6 and TNFα were observed in serum and tissue homogenates, correlating with reduced splenic Treg cell populations and increased inflammation and fibrosis in mesenteric and hepatic tissues. Chronic treatment with CGS21680 significantly reversed these pathological changes. Additionally, co-incubation of splenic Treg cells with CGS21680 mitigated apoptosis, cellular injury, and leakage in SVEC monolayers, thereby preserving their integrity. This treatment also led to reduced cytokine release and promoted a shift towards an M2 phenotype in RAW 264.7 macrophages. Overall, the A2AR agonist CGS21680 shows promise as a therapeutic agent to inhibit both adipose tissue inflammation and hepatic inflammation/fibrosis by disrupting pathogenic links between adipose tissue, mesenteric lymphatics, and splenic Treg cells in MASLD mice.

Keywords: A2A adenosine receptor (A2AR); Lymphatic hyperpermeability; Mesenteric and visceral adipose tissue; Metabolic dysfunction-associated steatotic liver disease; Splenic treg cells.