Figure 2. An integrated mechanistic scheme of liver immune activation against IRI.

In the first phase of liver IRI, the ischemia insult induces necrotic cell death, which in turn provide diverse “danger” molecules, such as HMGB1 and DNA fragments to activate innate TLR4, RAGE and TLR9 signaling on KCs/DCs and neutrophils. T cells, particularly CD4 Th1 effectors, may also facilitate local innate immune activation via CD154-CD40 pathway. In the second phase of liver IRI, IFN-γ produced by T cells, NKT and NK cells enhances innate immune activation. In addition, CD1d and CD39 activate NKT and NK cells, respectively. The activation progresses via positive and negative regulatory loops. The pro-inflammatory milieu, composed of TNF-α, IL-1β, IL-6, IL-12, CXCL10, CCL2, CXCL8 and ROS, further activates local and recruits circulating immune cells, which promote cytotoxicity against liver parenchymal cells. Meanwhile, IL-10 counter-regulates the sustained pro-inflammatory activation, whereas adenosine receptor 2A inhibits NKT cell activation. Type II NKT cells may also down-regulate IFN-γ production by pro-inflammatory type I NKT cells.