Please use this identifier to cite or link to this item: https://doi.org/10.1016/j.jhepr.2019.11.006
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dc.titleLiver fibrosis and CD206<sup>+</sup> macrophage accumulation are suppressed by anti-GM-CSF therapy
dc.contributor.authorTan-Garcia, A
dc.contributor.authorLai, F
dc.contributor.authorSheng Yeong, JP
dc.contributor.authorIrac, SE
dc.contributor.authorNg, PY
dc.contributor.authorMsallam, R
dc.contributor.authorTatt Lim, JC
dc.contributor.authorWai, LE
dc.contributor.authorTham, CYL
dc.contributor.authorChoo, SP
dc.contributor.authorLim, T
dc.contributor.authorYoung, DY
dc.contributor.authorD'Ambrosio, R
dc.contributor.authorDegasperi, E
dc.contributor.authorPerbellini, R
dc.contributor.authorNewell, E
dc.contributor.authorLe Bert, N
dc.contributor.authorGinhoux, F
dc.contributor.authorBertoletti, A
dc.contributor.authorChen, Q
dc.contributor.authorDutertre, CA
dc.date.accessioned2022-01-03T05:44:38Z
dc.date.available2022-01-03T05:44:38Z
dc.date.issued2020-02-01
dc.identifier.citationTan-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.issn25895559
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/212796
dc.description.abstractBackground & 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.publisherElsevier BV
dc.sourceElements
dc.subjectALT, alanine aminotransferase
dc.subjectBAMBI, BMP and Activin Membrane-bound Inhibitor
dc.subjectCD206+ macrophages
dc.subjectDAA, direct-acting antiviral
dc.subjectDC, dendritic cell
dc.subjectFFPE, formalin-fixed paraffin-embedded
dc.subjectGM-CSF
dc.subjectGM-CSF, granulocyte-macrophage colony-stimulating factor
dc.subjectHCC, hepatocellular carcinoma
dc.subjectHCV
dc.subjectHIER, heat-induced epitope retrieval
dc.subjectHSC, hepatic stellate cells
dc.subjectICS, intracellular cytokine staining
dc.subjectIntrahepatic macrophages
dc.subjectLPS, lipopolysaccharide
dc.subjectLSM, liver stiffness measurement
dc.subjectMS, multiple sclerosis
dc.subjectNASH
dc.subjectNASH, non-alcoholic steatohepatitis
dc.subjectPBMCs, peripheral blood mononuclear cells
dc.subjectRA, rheumatoid arthritis
dc.subjectSVR, sustained virological response
dc.subjectTCR, T cell receptor
dc.subjectTMA, tissue microarray
dc.subjectTNFα, tumour necrosis factor-α
dc.subjectTSA, tyramide signal amplification
dc.subjectanti-GM-CSF neutralizing antibody
dc.subjectfibrosis
dc.subjectmoMΦs, monocyte-derived macrophage-like cells
dc.subjectt-SNE, t-distributed stochastic neighbour embedding
dc.typeArticle
dc.date.updated2021-12-30T08:40:10Z
dc.contributor.departmentDEAN'S OFFICE (DUKE-NUS MEDICAL SCHOOL)
dc.contributor.departmentDEPT OF MEDICINE
dc.contributor.departmentMICROBIOLOGY AND IMMUNOLOGY
dc.contributor.departmentDUKE-NUS MEDICAL SCHOOL
dc.description.doi10.1016/j.jhepr.2019.11.006
dc.description.sourcetitleJHEP Reports
dc.description.volume2
dc.description.issue1
dc.description.page100062-
dc.published.statePublished
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