Innate Immune Regulations and Liver Ischemia-Reperfusion Injury

Abstract

Liver ischemia reperfusion activates innate immune system to drive the full development of inflammatory hepatocellular injury. Damage-associated molecular patterns (DAMPs) stimulate myeloid and dendritic cells via pattern recognition receptors (PRRs) to initiate the immune response. Complex intracellular signaling network transduces inflammatory signaling to regulate both innate immune cell activation and parenchymal cell death. Recent studies have revealed that DAMPs may trigger not only proinflammatory but also immune regulatory responses by activating different PRRs or distinctive intracellular signaling pathways or in special cell populations. Additionally, tissue injury milieu activates PRR-independent receptors which also regulate inflammatory disease processes. Thus, the innate immune mechanism of liver ischemia-reperfusion injury involves diverse molecular and cellular interactions, subjected to both endogenous and exogenous regulation in different cells. A better understanding of these complicated regulatory pathways/network is imperative for us in designing safe and effective therapeutic strategy to ameliorate liver ischemia-reperfusion injury in patients.

Fig. 1

Innate immune activation and regulation - A multi-cellular and -molecular interaction network. Liver innate immune activation involves multiple cells, including Kupffer cells/macrophages, neutrophils, dendritic cells, as well as hepatocytes. Initial hepatocellular damages due to ischemia result in releases of extracellular HMGB1, histone/DNA and ATP. These DAMPs stimulate different cells via TLR4/MD2, RAGE (by HMGB1) and TLR9, NLRP3 (by histone/DNA, ATP) to activate (+) or inhibit (−) liver inflammatory immune responses, leading to productions of cytokines/chemokines, ROSs, DAMPs (HMGB1, ATP) and cytotoxic molecules, including NETs by neutrophils. The proinflammatory milieu recruits and activate more innate and adaptive immune cells into inflamed livers and causes further hepatocellular damages; while immune regulatory milieu, such as IL-10, inhibits inflammation. Hepatocytes actively secrete HMGB1 upon TLR4 stimulation or IR stress. Resident and infiltrating DCs/macrophages respond to DAMPs differently. Rather than proinflammatory activation, resident DCs/macrophages produce IL-10 to inhibit tissue inflammation. Cells also upregulate CD24/Siglec, purinergic receptors (P1/P2) and CD39/CD73 upon inflammatory stimulation, which play immune regulatory roles in liver inflammation. CD39/CD73 converts ATP into adenosine, which binds to P1 receptors to facilitate M2 macrophage activation.