Kupffer cell dysfunction in liver cirrhosis leads to uncontrolled infection

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Infections contribute substantially to high mortality in patients with liver cirrhosis. Cirrhosis-associated immune dysfunction is a condition of insufficient immune response to pathogens on the one hand and increased basal immune activation on the other hand resulting in a multifaceted disturbance of the immune system. Physiologically the liver serves as a first-line defence to prevent systemic spreading of pathogens overcoming the intestinal barrier. Kupffer cells are liver resident macrophages with the unique capability to capture circulating pathogens, thus contributing essentially to the hepatic filtering function. The aim of the proposed research is to elucidate mechanisms of immune dysfunction in cirrhosis. We hypothesize that Kupffer cells in cirrhosis are impaired and therefore bacterial clearance and effective antibacterial immunity are reduced. Experimental cirrhosis in mice will be induced using different models of liver injury, e.g. CCl4 model which injures hepatocytes, bile duct ligation model and the DDC model of biliary injury. Once cirrhosis is established, mice will be infected with clinically relevant pathogens (Enterococcus species, E. coli, non-enterococcal streptococci, Staph. aureus). By using sophisticated intravital imaging to visualize Kupffer cells catching bacteria within the liver vasculature we hope to gain a better understanding of the underlying mechanisms in cirrhosis. Preliminary data suggest a significant impairment in pathogen catching by Kupffer cells, raising the possibility that certain molecules critical for pathogen catching (e.g. CRIg, TLR-4) are downregulated. This will be examined further using flow cytometry and mass cytometry. Next we will analyse the interplay of Kupffer cells with neutrophils in cirrhosis. Recruitment of neutrophils and formation of neutrophil extracellular traps (NETs) could be impaired in cirrhosis. The Kubes laboratory has recently identified a new mechanism of non-vascular recruitment of peritoneal repair macrophages, but it is unknown whether peritoneal macrophages have a role in infection. In a third step we will investigate the role of peritoneal macrophages in infection in healthy and injured livers. Pathological bacterial translocation is an important source of infections in patients with cirrhosis. For the second part of the proposed research, we plan to colonize the gut of cirrhotic mice with fluorescent bacteria. Intravital imaging of the intestine, draining lymph nodes and the liver of these mice will reveal the route pathogens take after crossing the epithelial barrier of the intestine and possibly systemic spreading to other organs. By imaging the liver with a focus on Kupffer cells and neutrophils we will explore a possible mechanism of defective barrier function of the liver in cirrhosis. Identifying the mechanisms will help to restore the balance of pro- and anti-inflammatory immune responses and as a result improve patients' prognosis.