Influence of hepatocytes on macrophage differentiation

The liver comprises the body's largest pool of macrophages constituting approximately 80% of all sessile tissue macrophages of the body. Thereby macrophages have a remarkable plasticity since their differentiation and function is continuously adapted to the microenvironment, which among others is defined by direct and indirect intercellular communication including communication via cell-cell contact and paracrine acting mediators. The present study investigates the impact of the intercellular communication between macrophages and hepatocytes on macrophage differentiation and function and involves a trans-well co-culture model in which cells are separated by a membrane that allows mediator exchange but not direct cellular interaction. The data indicate that co-cultivation with hepatocytes leads to a special phenotype of BMDM. This population of macrophages is characterized by the up-regulation of Gr-1, CD163, CD206, MHC class II and TLR4 as well as an increased expression of Arginase1, Stabilin1, CD16, CD32 and iNOS. These changes were accompanied by changes of the inflammatory response of BMDM towards LPS treatment, since co-culture with hepatocytes resulted in a significant increase of IL-10, IFNβ and Arginase1 expression and a reduced and/or less sustained expression of the cytokines TNFα, IL-6 and IL-12. Evidence is provided that hepatocytes and macrophages maintain a complex intercellular communication network resulting in a macrophage phenotype that is characterized by expression of markers indicative for wound-healing type sessile tissue macrophages displaying a predominant anti-inflammatory cytokine release upon activation with LPS characterized by an increase of the IL-10/IL-12 ratio.