File:Fimmu-09-02948-g001.jpg

English: Figure 1. Monocytes and macrophages in the immunopathology of acute and acute-on-chronic liver failure. (Left) Different causes lead to development of acute (bottom) and acute-on-chronic (top) liver failure. A major component of the immunopathology of both syndromes is liver inflammation initiated by release of various DAMPs and DAMPs/PAMPs, respectively. (Right) During these syndromes, there is a reciprocal interaction of the immune responses between the liver and systemic circulation throughout the different phases. Initiation phase: Kupffer cells become activated after recognition of PAMPs/DAMPs and initiate a pro-inflammatory response. Propagation phase: Bone-marrow derived monocytes are recruited to the liver and differentiate into inflammatory macrophages, expanding the macrophage pool and promoting tissue destruction. During the propagation phase, innate immune activation is self-perpetuating with recruitment of effector cells driving further cytokine and chemokine production; their release to systemic circulation provokes SIRS. These macrophage-derived mediators contribute to vascular endothelial dysfunction and microcirculatory disturbances, resulting in extra-hepatic organ dysfunction. In parallel to SIRS, a CARS develops that is due to release of anti-inflammatory mediators from the liver. Resolution/tissue-repair phase: In response to anti-inflammatory cytokines/mediators and efferocytosis of apoptotic cells, macrophages undergo functional reprogramming toward a pro-restorative phenotype, favoring resolution, and tissue recovery. “Spill over” of anti-inflammatory mediators from the liver to systemic circulation enhances CARS and causes monocyte functional reprogramming toward a pro-restorative phenotype, eventually leading to relative immunosuppression that predisposes susceptibility to infectious complications.