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Liver fibrosis and CD206(+) macrophage accumulation are suppressed by anti-GM-CSF therapy

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...

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Detalles Bibliográficos
Autores principales: Tan-Garcia, Alfonso, Lai, Fritz, Sheng Yeong, Joe Poh, Irac, Sergio E., Ng, Pei Y., Msallam, Rasha, Tatt Lim, Jeffrey Chun, Wai, Lu-En, Tham, Christine Y.L., Choo, Su P., Lim, Tony, Young, Dan Y., D'Ambrosio, Roberta, Degasperi, Elisabetta, Perbellini, Riccardo, Newell, Evan, Le Bert, Nina, Ginhoux, Florent, Bertoletti, Antonio, Chen, Qingfeng, Dutertre, Charles-Antoine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005658/
https://www.ncbi.nlm.nih.gov/pubmed/32039403
http://dx.doi.org/10.1016/j.jhepr.2019.11.006
Descripción
Sumario: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.