Cirrhosis of the liver is a systemic condition with raising prevalence, high morbidity and mortality and lack of therapeutic options other than transplantation. Infectious complications are independent predictors of prognosis being the leading cause of decompensation, liver failure and death. Infection susceptibility due to immuneparesis has been proposed to substantially accelerate progression of cirrhosis; underlying mechanisms remain underexplored. Currently development of targeted immune-modulatory therapy is debated. Recent work from my group discovered distinct subsets of the monocytic lineage in the circulation of patients with cirrhosis at different stages: Monocytic myeloid derived suppressor cells (M-MDSC) (Bernsmeier et al., 2018), immune-regulatory CD14+DR+AXL+ (Brenig et al., submitted) and CD14+MERTK+ cells (Bernsmeier et al., 2015a). In advanced stages of cirrhosis these dysfunctional subsets prevailed over regular monocytes, associated with reduced capacity to repel microbial challenge, infection susceptibility and adverse prognosis. Our proof-of-principle experiments verified enhanced innate immune function of these subsets by specific agonists and inhibitors, respectively. It is evident, that monocyte and tissue macrophage differentiation appears context specific. In line with this, we revealed a distinct diversity of monocytic cell differentiation (CD14+DR+AXL+; CD14+MERTK+) in the circulation and liver.Overall objectives: The primary objective is to systematically decipher the diversity of monocyte and macrophage differentiation in different compartments in patients with cirrhosis at different stages ex vivo on a transcriptional (scRNAseq), translational (FACS,IHC) and functional level (diverse methods). Specific aims The secondary aim is to dissect mechanisms of monocyte/ macrophage differentiation including the influence of diverse compartmental cells and soluble factors in in vitro models, and the longitudinal effect of bacterial infection and sterile inflammation in patients with cirrhosis ex vivo. The tertiary aim is to evaluate a potential translation to future immunotherapy using agents modulating monocyte and macrophage function in vitro and a murine model of fibrosis.Expected results and impact: We expect to identify the composition of functionally distinct monocyte/macrophage subsets in different compartments and stages of cirrhosis. Moreover we expect to understand the underlying context specific mechanisms, as well as systemic and compartmental effects of specific immune-modulatory agents. Detailed knowledge of the diversity, compartmentalisation and function of distinct subsets of the monocyte-macrophage lineage at different stages of cirrhosis enhances our understanding of the underlying complex pathophysiology and enables a valid discussion about possible immunotherapeutic strategies that may revert immune function, and reduce need for liver transplantation and death. Specific immune-modulatory agents targeting these monocyte/macrophage subsets (M-MDSC, CD14+DR+AXL+, CD14+MERTK) have been tested in pre-clinical studies in humans and a translation to patients with cirrhosis seems possible, if shown sensible in regards to compartment specific effects.