Control of macrophage repolarization and regulation of liver inflammation by HIF-1alpha and STAT3

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The liver harbours ~80% of all body macrophages and is also patrolled by myeloid cells such as blood monocytes, that continuously sense for pathogen-associated molecular patterns and eventually infiltrate into the liver. To avoid the adverse onset of immune responses under healthy steady state conditions physiological endotoxins levels derived from an intact microbiota are tolerated by the liver. However, to enable an efficient host defence to bacterial infection a tight regulation between inflammation and immunotolerance is needed. Activation of macrophage is herein a central step as this cell type is able to modulate the transitions between immunotolerance and host defence. We hypothesize that balancing pro- and anti-inflammatory responses of liver resident macrophages and an appropriate adaption of the inflammatory response during infection is controlled by IL-10 and transcriptional regulation by HIF1alpha and STAT3 in liver resident macrophages. We propose that IL-10 released by circulating monocytes is able to trigger a polarization shift of liver resident macrophages from a pro-inflammatory to an anti-inflammatory stage even in presence of pathogen associated patterns. In the resulting intermediate macrophage polarization phenotype the transcriptional regulators HIF-1alpha and STAT3 are proposed to control the inflammatory response by switching between oxidative respiration and glycolysis in order to facilitate an appropriate host defence and to avoid exaggerated inflammation and related liver tissue damage. We are planning to study the proposed mechanisms in a recently established human liver organoid model. This model was shown to mimic inflammation-related liver dysfunction as well as macrophage-related tissue repair that is able to restore liver organoid functionality during inflammation. We will specifically target defined events of the proposed signalling pathways by small molecule inhibitors and siRNA knock down of HIF1alpha and STAT3 and characterize cytokine release and bacterial phagocytosis ability after LPS stimulation in the organoid model. In mouse models of sepsis with a myeloid-specific knock-down of HIF-1alpha and STAT3 we will then subsequently verify our in vitro findings using the two more complex infection models with Staphylococcus aureus and polymicrobial peritoneal contamination and infection (PCI).The identification of key regulator proteins that control macrophage-associated inflammation will improve our understanding of inflammation-related liver dysfunction and could pave the way for new targeted strategies for the treatment of infectious liver disease.