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. Author manuscript; available in PMC: 2017 Dec 1.
Published in final edited form as: Transplantation. 2016 Dec;100(12):2601–2610. doi: 10.1097/TP.0000000000001411

Fig. 1.

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.