GDF15 Ameliorates Liver Fibrosis by Metabolic Reprogramming of Macrophages to Acquire Anti-Inflammatory Properties

Liver fibrosis/cirrhosis is significant health burden worldwide, resulting in liver failure or cancer and accounting for many deaths each year. The pathogenesis of liver fibrosis is very complex, which makes treatment challenging. Growth differentiation factor 15 (GDF15), a cysteine knot protein belonging to the transforming growth factor β (TGF-β) superfamily, has been shown to play a protective role after tissue injury and to promote a negative energy balance during obesity and diabetes. However, paucity of literature is available about GDF15 function in liver fibrosis. This study aimed to investigate the immunomodulatory role and therapeutic potential of GDF15 in progression of hepatic fibrosis.GDF15 expression was studied in patients with fibrosis/cirrhosis and in 2 murine models of liver fibrosis, including mice treated with CCl4 or DDC diet. GDF15 involvement in the pathogenesis of liver fibrosis was assessed in Gdf15 knockout mouse using both CCl4 and DDC diet experimental models. We used the CCl4 and/or DDC diet-induced liver fibrosis model to examine the antifibrotic and anti-inflammatory effects of AAV8-mediated GDF15 overexpression in hepatocytes or recombinant mouse GDF15.GDF15 expression is decreased in the liver of animal models and patients with liver fibrosis/cirrhosis compared with those without liver disease. In vivo studies showed that GDF15 deficiency aggravated CCl4 and DDC diet-induced liver fibrosis, while GDF15 overexpression mediated by AAV8 or its recombinant protein alleviated CCl4 and/or DDC diet-induced liver fibrosis. In Gdf15 knockout mice, the intrahepatic microenvironment that developed during fibrosis showed relatively more inflammation, as demonstrated by enhanced infiltration of monocytes and neutrophils and increased expression of proinflammatory factors, which could be diminished by AAV8-mediated GDF15 overexpression in hepatocytes. Intriguingly, GDF15 exerts its effects by reprogramming the metabolic pathways of macrophages to acquire an oxidative phosphorylation-dependent anti-inflammatory functional fate. Furthermore, adoptive transfer of GDF15-preprogrammed macrophages to mouse models of liver fibrosis induced by CCl4 attenuated inflammation and alleviated the progression of liver fibrosis.GDF15 ameliorates liver fibrosis via modulation of liver macrophages. Our data implicate the importance of the liver microenvironment in macrophage programming during liver fibrosis and suggest that GDF15 is a potentially attractive therapeutic target for the treatment of patients with liver fibrosis.