Hepatocytes paradoxically affect intrahepatic IFN-γ production in autoimmune hepatitis due to Gal-9 expression and TLR2/4 ligand release

Mo, Ran; Feng, Xiang; Wu, Yanan; Wang, Han; He, Yongpei; Sun, Huanhuan; Guo, Fang; Chen, Qian; Yan, Wei; Li, Peiyuan; Liu, Mei; Zhang, Guimei; Tian, Dean; Feng, Zuo-Hua

doi:10.1016/j.molimm.2020.05.014

Cited by 11 publications

(6 citation statements)

References 58 publications

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“…Furthermore, infiltration of CXCR3+ inflammatory monocytes is decreased in IFNgR -/- livers, particularly when IFN-γ-R is absent in the bone marrow, suggesting a non-hematopoietic intrinsic role for IFN-γ induced CXCL9 in monocyte recruitment ( S5C and S5D Fig ). In addition, transcripts of Mixed lineage kinase domain like pseudokinase gene ( MLKL) , which is a known mediator of hepatocyte death induced by IFN-γ, were increased in IFNgR +/+ livers, indicative of direct IFN-γ mediated hepatocyte injury ( Fig 5A and S2 Table ) [ 28 , 29 ]. This result confirmed a differential IFN-γ response in livers that were receptor sufficient ( IFNgR +/+ ) compared to deficient ( IFNgR -/- ).…”

Section: Resultsmentioning

confidence: 99%

“…Hepatocytes are known to express IFN-γ-R, which assists in innate and type 1 immune response to hepatotropic viruses and other environmental insults to which mammals are exposed [ 12 , 38 ]. The hepatic response is involved in cell death, recruitment of leukocytes, inhibition of fibrosis and metabolic changes [ 12 , 28 , 29 , 38 ]. Prencipe et al described a hepatic upregulation in transcription of genes involved in the IFN-γ pathway in children suffering from secondary hemophagocytic lymphohistiocytosis (HLH) with hepatitis, supporting the hypothesis that hepatocyte IFN-γ response could contribute to liver injury in HLH [ 3 ].…”

Section: Discussionmentioning

confidence: 99%

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Familial hemophagocytic lymphohistiocytosis hepatitis is mediated by IFN-γ in a predominantly hepatic-intrinsic manner

et al. 2022

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Interferon gamma (IFN-γ) is the main cytokine driving organ dysfunction in Familial Hemophagocytic Lymphohistiocytosis (FHL). Blockade of IFN-γ pathway ameliorates FHL hepatitis, both in animal models and in humans with FHL. Hepatocytes are known to express IFN-γ receptor (IFN-γ-R). However, whether IFN-γ induced hepatitis in FHL is a lymphocyte or liver intrinsic response to the cytokine has yet to be elucidated. Using a IFNgR−/− bone marrow chimeric model, this study showed that non-hematopoietic IFN-γ response is critical for development of FHL hepatitis in LCMV-infected Prf1−/− mice. Lack of hepatic IFN-γ responsiveness results in reduced hepatitis as measured by hepatomegaly, alanine aminotransferase (ALT) levels and abrogated histologic endothelial inflammation. In addition, IFN-γ non-hematopoietic response was critical in activation of lymphocytes by soluble interleukin 2 receptor (sIL-2r) and recruitment of CD8+ effector T lymphocytes (CD8+ CD44hi CD62Llo) (Teff) and inflammatory monocytes. Lastly, non-hematopoietic IFN-γ response results in increased hepatic transcription of type 1 immune response and oxidative stress response pathways, while decreasing transcription of genes involved in extracellular matrix (ECM) production. In summary, these findings demonstrate that there is a hepatic transcriptional response to IFN-γ, likely critical in the pathogenesis of FHL hepatitis and hepatic specific responses could be a therapeutic target in this disorder.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Familial hemophagocytic lymphohistiocytosis hepatitis is mediated by IFN-γ in a predominantly hepatic-intrinsic manner

et al. 2022

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“…TLR4/TRIF/NF‐κB is a classic signalling cascade, which mediated chronic inflammation and lipid disorders in non‐alcoholic fatty liver 34–36 . Furthermore, a report indicated that early blocking of TLR2/4 ligand can effectively reduce liver damage caused by AIH 37 . Therefore, we explored the relationship between MARCO and TLR4/TRIF/NF‐κB pathway in AIH.…”

Section: Disccusionmentioning

confidence: 99%

“…34 , 35 , 36 Furthermore, a report indicated that early blocking of TLR2/4 ligand can effectively reduce liver damage caused by AIH. 37 Therefore, we explored the relationship between MARCO and TLR4/TRIF/NF‐κB pathway in AIH. After antagonizing MARCO in AIH, the protein expression of TLR4 was decreased, which further affects the downstream TRIF/NF‐κB pathway and alleviates the progression of the disease.…”

Section: Disccusionmentioning

confidence: 99%

Polyguanine alleviated autoimmune hepatitis through regulation of macrophage receptor with collagenous structure and TLR4‐TRIF‐NF‐κB signalling

Cai

Xia

et al. 2022

J Cellular Molecular Medi

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Autoimmune hepatitis (AIH) is a progressive and chronic inflammatory disease in the liver. MARCO is a surface receptor of macrophage involving in tissue inflammation and immune disorders. Moreover, polyguanine (PolyG) is considered to bind to macrophage receptor with collagenous structure (MARCO). However, the role of MARCO and PolyG in the development and treatment of AIH still remains unclear. Therefore, this study explores the expression of MARCO and therapeutic activity of PolyG in both S100-induced AIH in mouse and Lipopolysaccharide (LPS)-treated macrophage (RAW264.7 cells). Moreover, there were significant increases in inflammatory factors and MARCO, as well as decrease in I-kappa-B-alpha (Ik-B) in the liver of AIH mice and LPS-induced cells. However, PolyG treatment significantly reversed the elevation of inflammatory cytokins, MARCO and reduction of Ik-B. In addition, PolyG treatment could downregulate the expression of Toll-like receptor 4 (TLR4) and TIR-domaincontaining adaptor inducing interferonβ (TRIF), decrease macrophage M1 polarization and increase macrophage M2 polarization. When hepatocytes were co-cultured with different treatment of macrophages, similar expression profile of inflammatory cytokines was observed in hepatocytes. The research revealed that MARCO expression was elevated in AIH mice. PolyG treatment and inhibition of MARCO significantly reduced inflammatory cytokines expression in the liver as well as hepatocytes and macrophages. Therefore, MARCO could be a target for the treatment of AIH.

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“…Along with the deepening of the research, a complicated network of signal transduction pathways referring to provoking or exacerbating the impairment of liver function in this model was gradually disclosed, including “Toll like receptor (TLR) signaling pathway” [ 51 , 52 ], “MAPK signaling pathway” [ 53 ], “PI 3 K/Akt signaling pathway” [ 54 , 55 ], “Ferroptosis” [ 56 ], “Notch signaling pathway” [ 57 ], “Wnt signaling pathway” [ 58 , 59 ], “Endocytosis” [ 60 ], and so on. The data in one of our earlier experiments also showed that the differentially expressed mRNAs (DEMs) filtered out by microarray with this model were significantly enriched in these pathways [ 61 ].…”

Section: Intricate Signal Transduction Pathways Involved In the Patho...mentioning

confidence: 99%

Concanavalin A-induced autoimmune hepatitis model in mice: Mechanisms and future outlook

Liu

Hou

2022

Open Life Sciences

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The concanavalin A (Con A)-induced liver injury mouse model is a typical animal model focusing on T cell-dependent hepatic damage in the field of autoimmune hepatitis (AIH). However, the underlying mechanism of hepatic dysfunction due to cell activation or signaling pathways triggered by Con A has not been fully clarified. Therefore, the controversy on this model remains in the academic community. In this article, we first summarized the merit and demerit of this contentious model from the perspectives of cell dysfunction, microcirculation disturbance, involved signaling pathways, as well as the properties of Con A. Then, we summed up the scientific implications of the model in elucidating the pathogenesis of AIH, and the shortcomings of this model were also summarized to elucidate the pathogenesis and application prospect of this classical liver injury mouse model in the study of AIH.

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Hepatocytes paradoxically affect intrahepatic IFN-γ production in autoimmune hepatitis due to Gal-9 expression and TLR2/4 ligand release

Cited by 11 publications

References 58 publications

Familial hemophagocytic lymphohistiocytosis hepatitis is mediated by IFN-γ in a predominantly hepatic-intrinsic manner

Familial hemophagocytic lymphohistiocytosis hepatitis is mediated by IFN-γ in a predominantly hepatic-intrinsic manner

Polyguanine alleviated autoimmune hepatitis through regulation of macrophage receptor with collagenous structure and TLR4‐TRIF‐NF‐κB signalling

Concanavalin A-induced autoimmune hepatitis model in mice: Mechanisms and future outlook

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