Hepatocytes: A key role in liver inflammation

Abstract

Hepatocytes, the major parenchymal cells in the liver, are responsible for a variety of cellular functions including carbohydrate, lipid and protein metabolism, detoxification and immune cell activation to maintain liver homeotasis. Recent studies show hepatocytes play a pivotal role in liver inflammation. After receiving liver insults and inflammatory signals, hepatocytes may undergo organelle damage, and further respond by releasing mediators and expressing molecules that can act in the microenvironment as well as initiate a robust inflammatory response. In this review, we summarize how the hepatic organelle damage link to liver inflammation and introduce numerous hepatocyte-derived pro-inflammatory factors in response to chronic liver injury.

Keywords: cytokines; extracellular vesicles; hepatic inflammation; hepatocyte; organelle damage.

Figure 1

Role of ER stress in liver inflammation. Multiple stimuli lead to the activation of UPR response in hepatocyte. The three ER transmembrane sensors, PERK, IRE1 and ATF6, coordinately through downstream signaling cascades to resolve the protein folding defect and promote cell survival. If the adaptive UPR is overwhelmed by sustained or massive ER stress, it leads to hepatocyte steatosis and death. Meanwhile, ER stress may trigger NFκB and JNKs activation, resulting in release of proinflammatory cytokines. On the other hand, ER stress can induce CHOP-dependent NLRP3 inflammasome activation in hepatocytes. Besides, activation of IRE1A in hepatocytes promotes the release of inflammatory extracellular vesicles (EVs), thereby accummulating immune cells infiltration.

Figure 2

Role of mitochondrial damage in liver inflammation. Various liver injury impair mitochondrial respiration and increase ROS formation, cause mtDNA damage. High levels of ROS can increase synthesis of cytokines, which cause apoptosis and necrosis of hepatocytes. The presence of mtDNA in the cytosol or circulation can trigger proinflammatory and type I IFN responses. Moreover, release of mitochondria-derived danger signals, such as mtDNA, formylated proteins, can attract macrophage and neutrohphils, resulting in activation of NFκB and NLRP3 inflammasome. MtDNA also promotes fibrogenic activation of HSCs. Besides, reduced expression of mitochondrial protein Mfn2 leads to deficient ER-mitochondrial phosphatidylserine transfer, which provokes liver inflammation. HBV and HCV can activate innate immune antiviral signaling and inflammatory pathways through induction of type I interferons and expression of inflammatory cytokines by NFκB.