Regulation of Kupffer Cell Activation by Hepatic Stellate Cells

Abstract

When cells in the liver are damaged or killed by trauma, macrophages become activated to release cytokines and phagocytose dead cell debris, which facilitates liver repair. The mechanisms that regulate macrophage activation after liver damage remain poorly understood. We found previously that the transcription factor hypoxia‐inducible factor‐1a (HIF‐1a) is activated in hepatic stellate cells (HSCs) after injury. Deletion of HIF‐1a in HSCs prevented hepatic macrophages from polarizing to an M1 phenotype after liver injury, which reduced production of proinflammatory cytokines and prevented removal of dead cell debris. In the present study, we tested the hypothesis that necrotic hepatocytes activate HIF‐1a in HSCs, which regulates release of a mediator that in turn activates Kupffer cells. In our current studies, we show that HIF‐1a is activated and HIF‐1a target genes are upregulated in HSCs exposed to necrotic hepatocytes. Our data reveal further that exposure of HSCs to necrotic hepatocytes also activates several MAPK pathways, including ERK1/2 and p38, and upregulates the chemokines CCL2, CCL7, and CCL9. Finally, we demonstrate that treatment of Kupffer cells with conditioned medium from HSCs treated with necrotic hepatocytes upregulates the proinflammatory genes CXCL1 and CXCL2 and down‐regulates the anti‐inflammatory gene IL‐10. Together, these data support the mechanism whereby necrotic cells activate HIF‐1a in HSCs, which upregulates a mediator that is released. This mediator then stimulates Kupffer cells to produce proinflammatory cytokines and to phagocytose dead cell debris. These studies could help identify novel targets for reducing liver injury and improving liver repair by modulating the hepatic inflammatory response.