**3. Tolerogenic milieu of the liver**

The liver is a metabolic organ with a principal role of the detoxification and nutrient storage, but also protein synthesis and production of biochemicals required for the digestion and growth.

Without a doubt, the liver is also an important element of the immune system. A broad range of parts of innate and adaptive immunity is synthesized inside like acute-phase proteins, cytokines, complement components etc. Indeed, the cells that populate the liver encompass not only those with metabolic function. A great variety of immune cells are found in the parenchyma. Liver sinusoidal endothelial cells (LSECs), Kupffer cells, dendritic cells, hepatic stellate cells (HSCs), natural killer (NK) cells, NKT cells and T cells are present in the liver interstitium. In addition, hepatic cells express surface receptors immanent for the innate immunity [11]. Altogether, they participate in the establishment of a particular milieu that

from one hand tolerates a broad range of gut-derived antigens continuously passing across and on the other hand, retain the capacity to set up an immune response against pathogens like bacteria and viruses.

The questions of how this community maintains an immunotolerant environment to nutritional antigens, provide effector response to pathogens and guarantee liver transplantation are of particular interest. Moreover, the graft rejection is relatively rare in LT as compared to other SOT.

The combination of particular anatomy, variety of cells, specific expression of HLA molecules [12] and sustained antigenic stimulation makes the liver a unique immunologic structure. The blood delivered by vena portae is rich in alimentary and other antigens, which in fact are tolerated by the healthy liver. Indeed, the basal levels of pro- and anti-inflammatory cytokines are constant, but change under pathologic conditions in etiology-dependent manner [13–15].

The liver primarily is a metabolic organ and this function significantly impacts its immunologic reactivity. The metabolism of carbohydrates and lipids has a particular impact. Absorbed by hepatocytes, they are collected as glycogen and lipoproteins. Further on, cholesterol, triglycerides and other intermediate metabolites can trigger TLR signalization and inflammasome activation. The final result is the increased pro-inflammatory cytokines secretion followed by the initiation of different pathologic phenomena, liver fibrosis for example [16]. Another example demonstrates that metabolic variations in hepatocytes during hepatitis B and C infection can raise viral replication [17, 18].

Together with hepatocytes, dendritic cells and macrophages also participate in the hepatic cytokine regulation. The oxidative phosphorylation may switch to anaerobic glycolysis (effect Warburg) leading to stimulation of pro-inflammatory mediators synthesis [19, 20]. Succinate dehydrogenase can additionally influence the cytokine balance. Its high levels may activate Hypoxia induced factor-1 (HIF-1) and production of IL-1β, thus providing evidence for the direct communication between the cellular metabolism and inflammatory response [21]. IL-1β per se is an important player in the control of homeostasis by regulating sleep, feeding, temperature in healthy conditions [22]. In pathologic situations, IL-1β is a critical mediator of the inflammatory response through processing of pro-IL-1β by Caspase-1 via inflammasome [23, 24]. Other mechanisms can be also involved in the cleavage of pro-IL-1β into biologically active IL-1b. Among them are serine proteases-neutrophil elastase, proteinase 3, cathepsin G in neutrophils [25–27] and the spontaneous release of IL-1β following pyroptosis and necroptosis [28]. Not surprisingly, IL-1β levels were found increased in other, relatively frequent medical conditions like NAFLD [29].
