Hepatocytes secret a mediator pattern that induces macrophage phenotype with properties of wound healing type and regulatory macrophages

Introduction: 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 cell-cell contact and paracrine acting mediators. Up to now the complex network that determines the differentiation and function of liver macrophages and the impact of the intercellular communication between macrophages and the other parenchymal and non-parenchymal cell types of the liver is not well understood.

Objectives: The present study investigates the role of the intercellular communication between macrophages and hepatocytes on macrophage differentiation and function. Under physiological conditions the sinusoidal endothelial cell layer and the space of Dissé separate macrophages and hepatocytes from each other. Therefore the study focuses on the impact of the intercellular communication via soluble mediators on the differentiation of bone marrow derived macrophages (BMDM) employing co-culture models with highly purified primary murine hepatocytes embedded in a sandwich collagen matrix.

Results: Evidence is provided that in the presence of hepatocytes BMDM times dependently differentiate into a macrophage population that is characterized by the up-regulation of Gr-1, CD163, CD206, MHC class II and TLR4. In particular with respect to CD163 and CD206 this expression profile closely resembles to that of macrophages derived from the liver (Kupffer cells). These changes essentially depend on direct co-culture and were accompanied by alterations of the inflammatory response of co-cultured macrophages towards LPS treatment with increased expression of IL-10 and IFNβ and a reduced and/or less sustained expression of TNFα, IL-6 and IL-12.

Conclusion: The data provided indicate that the intercellular communication of hepatocytes and macrophages results in macrophages characterized by the 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.

Corresponding author: Bode, Johannes G.

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