Please use this identifier to cite or link to this item:
https://doi.org/10.1016/j.jhepr.2019.11.006
DC Field | Value | |
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dc.title | Liver fibrosis and CD206<sup>+</sup> macrophage accumulation are suppressed by anti-GM-CSF therapy | |
dc.contributor.author | Tan-Garcia, A | |
dc.contributor.author | Lai, F | |
dc.contributor.author | Sheng Yeong, JP | |
dc.contributor.author | Irac, SE | |
dc.contributor.author | Ng, PY | |
dc.contributor.author | Msallam, R | |
dc.contributor.author | Tatt Lim, JC | |
dc.contributor.author | Wai, LE | |
dc.contributor.author | Tham, CYL | |
dc.contributor.author | Choo, SP | |
dc.contributor.author | Lim, T | |
dc.contributor.author | Young, DY | |
dc.contributor.author | D'Ambrosio, R | |
dc.contributor.author | Degasperi, E | |
dc.contributor.author | Perbellini, R | |
dc.contributor.author | Newell, E | |
dc.contributor.author | Le Bert, N | |
dc.contributor.author | Ginhoux, F | |
dc.contributor.author | Bertoletti, A | |
dc.contributor.author | Chen, Q | |
dc.contributor.author | Dutertre, CA | |
dc.date.accessioned | 2022-01-03T05:44:38Z | |
dc.date.available | 2022-01-03T05:44:38Z | |
dc.date.issued | 2020-02-01 | |
dc.identifier.citation | Tan-Garcia, A, Lai, F, Sheng Yeong, JP, Irac, SE, Ng, PY, Msallam, R, Tatt Lim, JC, Wai, LE, Tham, CYL, Choo, SP, Lim, T, Young, DY, D'Ambrosio, R, Degasperi, E, Perbellini, R, Newell, E, Le Bert, N, Ginhoux, F, Bertoletti, A, Chen, Q, Dutertre, CA (2020-02-01). Liver fibrosis and CD206<sup>+</sup> macrophage accumulation are suppressed by anti-GM-CSF therapy. JHEP Reports 2 (1) : 100062-. ScholarBank@NUS Repository. https://doi.org/10.1016/j.jhepr.2019.11.006 | |
dc.identifier.issn | 25895559 | |
dc.identifier.uri | https://scholarbank.nus.edu.sg/handle/10635/212796 | |
dc.description.abstract | Background & Aims: Chronic liver inflammation leads to fibrosis and cirrhosis and is associated with an accumulation of intrahepatic TNFα-secreting CD206+ macrophages, which may participate in maintaining chronic liver disease in a GM-CSF-dependent manner. We aimed to elucidate the exact role of GM-CSF in the development and progression of chronic liver disease. Methods: Liver immunohistochemistry and serum quantification were performed in patients with viral and non-viral-related liver disease to compare CD206+ monocyte/macrophages, fibrosis and GM-CSF. This was followed by functional validations in vitro and in vivo in humanised mice. Results: Using multiplex immunofluorescence and histo-cytometry, we show that highly fibrotic livers had a greater density of CD206+ macrophages that produced more TNFα and GM-CSF in the non-tumour liver regions of patients with hepatocellular carcinoma (n = 47), independent of aetiology. In addition, the absolute number of CD206+ macrophages strongly correlated with the absolute number of GM-CSF-producing macrophages. In non-HCC chronic HCV+ patients (n = 40), circulating GM-CSF levels were also increased in proportion to the degree of liver fibrosis and serum viral titres. We then demonstrated in vitro that monocytes converted to TNFα-producing CD206+ macrophage-like cells in response to bacterial products (lipopolysaccharide) in a GM-CSF-dependent manner, confirming the in vivo normalisation of serum GM-CSF concentration following oral antibiotic treatment observed in HBV-infected humanised mice. Finally, anti-GM-CSF neutralising antibody treatment reduced intrahepatic CD206+ macrophage accumulation and abolished liver fibrosis in HBV-infected humanised mice. Conclusions: While the direct involvement of CD206+ macrophages in liver fibrosis remains to be demonstrated, these findings show that GM-CSF may play a central role in liver fibrosis and could guide the development of anti-GM-CSF antibody-based therapy for the management of patients with chronic liver disease. Lay summary: Liver fibrosis is a major driver of liver disease progression. Herein, we have shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) plays an important role in the development of liver fibrosis. Our findings support the use of anti-GM-CSF neutralising antibodies for the management of patients with chronic liver disease resulting from both viral and non-viral causes. | |
dc.publisher | Elsevier BV | |
dc.source | Elements | |
dc.subject | ALT, alanine aminotransferase | |
dc.subject | BAMBI, BMP and Activin Membrane-bound Inhibitor | |
dc.subject | CD206+ macrophages | |
dc.subject | DAA, direct-acting antiviral | |
dc.subject | DC, dendritic cell | |
dc.subject | FFPE, formalin-fixed paraffin-embedded | |
dc.subject | GM-CSF | |
dc.subject | GM-CSF, granulocyte-macrophage colony-stimulating factor | |
dc.subject | HCC, hepatocellular carcinoma | |
dc.subject | HCV | |
dc.subject | HIER, heat-induced epitope retrieval | |
dc.subject | HSC, hepatic stellate cells | |
dc.subject | ICS, intracellular cytokine staining | |
dc.subject | Intrahepatic macrophages | |
dc.subject | LPS, lipopolysaccharide | |
dc.subject | LSM, liver stiffness measurement | |
dc.subject | MS, multiple sclerosis | |
dc.subject | NASH | |
dc.subject | NASH, non-alcoholic steatohepatitis | |
dc.subject | PBMCs, peripheral blood mononuclear cells | |
dc.subject | RA, rheumatoid arthritis | |
dc.subject | SVR, sustained virological response | |
dc.subject | TCR, T cell receptor | |
dc.subject | TMA, tissue microarray | |
dc.subject | TNFα, tumour necrosis factor-α | |
dc.subject | TSA, tyramide signal amplification | |
dc.subject | anti-GM-CSF neutralizing antibody | |
dc.subject | fibrosis | |
dc.subject | moMΦs, monocyte-derived macrophage-like cells | |
dc.subject | t-SNE, t-distributed stochastic neighbour embedding | |
dc.type | Article | |
dc.date.updated | 2021-12-30T08:40:10Z | |
dc.contributor.department | DEAN'S OFFICE (DUKE-NUS MEDICAL SCHOOL) | |
dc.contributor.department | DEPT OF MEDICINE | |
dc.contributor.department | MICROBIOLOGY AND IMMUNOLOGY | |
dc.contributor.department | DUKE-NUS MEDICAL SCHOOL | |
dc.description.doi | 10.1016/j.jhepr.2019.11.006 | |
dc.description.sourcetitle | JHEP Reports | |
dc.description.volume | 2 | |
dc.description.issue | 1 | |
dc.description.page | 100062- | |
dc.published.state | Published | |
Appears in Collections: | Staff Publications Elements |
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