Diosmetin alleviates TNFα-induced liver inflammation by improving liver sinusoidal endothelial cell dysfunction

Abstract

Sterile inflammation contributes to the development of many liver diseases including non-alcoholic fatty liver disease. Tumor necrosis factor alpha (TNFα) is a key cytokine driving liver inflammation primarily through pro-inflammatory activation of liver sinusoidal endothelial cells (LSEC). The knowledge of whether modulating LSEC activation can alleviate liver inflammation is scarce. This study aims to establish and validate an animal model mimicking LSEC dysfunction observed in obese patients with elevated plasma levels of TNFα, and explore whether vasoactive flavonoid diosmetin could serve as a therapeutic agent for liver inflammation by modulation of LSEC dysfunction. Obese patients with elevated plasma levels of TNFα, LSEC dysfunction and liver inflammation had also reduced Mcpip1 expression in peripheral blood mononuclear cells. Mcpip1 is a protein that negatively regulates the levels of pro-inflammatory cytokines. To model this, we generated mice with Mcpip1 knock-out in myeloid cells (Mcpip1^fl/flLysM^Cre), which displayed systemic and liver inflammation like that observed in patients. Diosmetin treatment efficiently reduced TNFα-dependent LSEC activation in vitro and in vivo, and reduced liver inflammation in Mcpip1^fl/flLysM^Cre mice without affecting systemic inflammation. Diosmetin's effects may stem from inhibiting NF-κB pathway in TNFα-activated endothelial cells. Our findings demonstrate that the Mcpip1^fl/flLysM^Cre mouse model is useful for studying new anti-inflammatory therapies for the liver. We show that diosmetin, a vasoactive flavonoid used in the clinic to treat chronic venous insufficiency, also has strong anti-inflammatory properties in the liver. These results indicate that diosmetin has the potential to be further investigated as a supportive therapy for liver inflammation in humans.

Keywords: Cell adhesion molecules; Diosmetin; Glycocalyx; LSEC; Liver inflammation; Mcpip1; TNFα.