Aldehyde dehydrogenase 2 suppresses cirrhosis and alcohol-induced hepatocellular carcinoma via the inhibition of acetaldehyde-derived DNA damage and multiple oncogenic signaling pathways

Objective:Hepatocellular carcinoma(HCC)is the most common primary liver cancer,the fifth most common cancer and the third most common global cause of cancer related deaths.Chronic alcohol consumption is a well-known risk factor for HCC.Acetaldehyde,a main metabolite of ethanol oxidation.

Immunopathobiology and therapeutic targets related to cytokines in liver diseases

Chronic liver injury with any etiology can progress to fibrosis and the end-stage diseases cirrhosis and hepatocellular carcinoma.The progression of liver disease is controlled by a variety of factors,including liver injury,inflammatory cells,inflammatory mediators,cytokines,and the gut microbiome.In the current review,we discuss recent data on a large number of cytokines that play important roles in regulating liver injury,inflammation,fibrosis,and regeneration,with a focus on interferons and T helper(Th)1,Th2,Th9,Th17,interleukin(IL)-1 family,IL-6 family,and IL-20 family cytokines.Hepatocytes can also produce certain cytokines(such as IL-7,IL-11;and IL-33),and the functions of these cytokines in the liver are briefly summarized.Several cytokines have great therapeutic potential,and some are currently being tested as therapeutic targets in clinical trials for the treatment of liver diseases,which are also described.

Invariant natural killer T cells contribute to chronic-plus-binge ethanol-mediated liver injury by promoting hepatic neutrophil infiltration

Neutrophil infiltration is a hallmark of alcoholic steatohepatitis; however, the underlying mechanisms remain unclear. We previously reported that chronic-plus-binge ethanol feeding synergistically induces hepatic recruitment of neutrophils, which contributes to liver injury. In this paper, we investigated the roles of invariant natural killer T （iNKT） cells in chronic-plus-binge ethanol feeding-induced hepatic neutrophil infiltration and liver injury. Wild-type and two strains of iNKT cell-deficient mice （CDld- and Ja18-deficient mice） were subjected to chronic-plus-binge ethanol feeding. Liver injury and inflammation were examined. Chronic-plus-binge ethanol feeding synergistically increased the number of hepatic iNKT cells and induced their activation, compared with chronic feeding or binge alone, iNKT cell-deficient mice were protected from chronic-plus-binge ethanol-induced hepatic neutrophil infiltration and liver injury. Moreover, chronic-plus-binge ethanol feeding markedly upregulated the hepatic expression of several genes associated with inflammation and neutrophil recruitment in wild-type mice, but induction of these genes was abrogated in iNKT cell-deficient mice. Importantly, several cytokines and chemokines （e.g., MIP-2, MIP-1, IL-4, IL-6 and osteopontin） involved in neutrophil infiltration were upregulated in hepatic NKT cells isolated from chronic-plus-binge ethanol-fed mice compared to pair-fed mice. Finally, treatment with CDld blocking antibody, which blocks iNKT cell activation, partially prevented chronic-plus-binge ethanol-induced liver injury and inflammation. Chronic-plus-binge ethanol feeding activates hepatic iNKT cells, which play a critical role in the development of early alcoholic liver injury, in part by releasing mediators that recruit neutrophils to the liver, and thus, iNKT cells represent a potential therapeutic target for the treatment of alcoholic liver disease.

Kupffer cell restoration after partial hepatectomy is mainly driven by local cell proliferation in IL-6-dependent autocrine and paracrine manners

Kupffer cells(KCs),which are liver-resident macrophages,originate from the fetal yolk sac and represent one of the largest macrophage populations in the body.However,the current data on the origin of the cells that restore macrophages during liver injury and regeneration remain controversial.Here,we address the question of whether liver macrophage restoration results from circulating monocyte infiltration or local KC proliferation in regenerating livers after partial hepatectomy(PHx)and uncover the underlying mechanisms.By using several strains of genetically modified mice and performing immunohistochemical analyses,we demonstrated that local KC proliferation mainly contributed to the restoration of liver macrophages after PHx.Peak KC proliferation was impaired in Il6-knockout(KO)mice and restored after the administration of IL-6 protein,whereas KC proliferation was not affected in Il4-KO or Csf2-KO mice.The source of IL-6 was identified using hepatocyte-and myeloid-specific Il6-KO mice and the results revealed that both hepatocytes and myeloid cells contribute to IL-6 production after PHx.Moreover,peak KC proliferation was also impaired in myeloid-specific Il6 receptor-KO mice after PHx,suggesting that IL-6 signaling directly promotes KC proliferation.Studies using several inhibitors to block the IL-6 signaling pathway revealed that sirtuin 1(SIRT1)contributed to IL-6-mediated KC proliferation in vitro.Genetic deletion of the Sirt1 gene in myeloid cells,including KCs,impaired KC proliferation after PHx.In conclusion,our data suggest that KC repopulation after PHx is mainly driven by local KC proliferation,which is dependent on IL-6 and SIRT1 activation in KCs.

Interleukin-22 in the pathogenesis and potential treatment of liver diseases

Interleukin(IL)-22,a member of the IL-10 cytokine family,plays critical roles in tissue repair and host defense.IL-22 binds to its hetereodimeric receptor(R)composed of IL-22R1 and IL-10R2 and activates downstream signaling,including Signal transducer and activator of transcription 3(STAT3)pathways.IL-22 promotes the expression of survival genes in a STAT3-dependent manner.IL-22R1 expression is restricted mainly in epithelial cells while IL-10R2 is ubiquitously expressed in almost all cell types.In the liver,IL-22R1 is expressed in hepatocytes,liver progenitor cells,hepatic stellate cells and liver cancer cells.IL-22 protects the liver in various liver damage models and promotes liver regeneration after liver injury.IL-22 also helps to resolve liver fibrosis by inducing hepatic stellate cell senescence.IL-22 is considered a pro-inflammatory cytokine in viral hepatitis although it does not directly act on immune cells.IL-22 is reported to be involved in the development of liver cancer and in regulating energy metabolism.Studies on IL-22 in liver inflammation,injury and repair will provide valuable information to clarify IL-22 as a potential candidate for treating liver injury and fibrosis.

From basic liver immunology to therapeutic opportunities for liver diseases

Five years ago,we launched a special issue in the Cellular&Molecular Immunology with a focus on basic liver immunology,which included eight review articles covering the knowledge about immunological features of the liver.1 To date,these articles have been cited more than 1200 times according to the Google Scholar.Over the past 5 years,enormous progress has been made in the understanding of liver immunology and the identification of various therapeutic strategies targeting inflammatory mediators for the diagnosis and treatment of liver diseases.Therefore,we are honored and excited to present another follow-up special issue to discuss the updated knowledge of translational liver immunology and the therapeutic targets based on the knowledge we learned from the studies of liver immunology.

The alteration of immune cells in the pathogenesis of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis

The prevalence of non-alcoholic fatty liver disease(NAFLD)increases rapidly in recent decades.NAFLD has become a major public health problem in China and the whole world,and it is considered as the main cause for the chronic liver diseases.However,there is still not specific and effective treatment for non-alcoholic steatohepatitis(NASH),the advanced form of NAFLD.The inflammation in the liver is the hallmark of NASH.Actually,the dysregulation of immune cells happened in the early stage of NAFLD.Targeting immune cells in the liver may represent one of the effective ways for NASH treatment.A better understanding of the change of immune cells in the pathogenesis of NAFLD will be very helpful for developing new treatments for NAFLD and NASH.Here we summarized how the immune cells were affected in different stages of NAFLD and how these immune cells contributed to the development of NAFLD.