Liver fibrosis and CD206 macrophage accumulation are suppressed by anti-GM-CSF therapy.

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ID: 94060
2020
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Abstract
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.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 and in humanised mice.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 that monocytes converted to TNFα-producing CD206 macrophage-like cells in response to bacterial products (lipopolysaccharide) in a GM-CSF-dependent manner, confirming the 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.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.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.
Reference Key
tangarcia2020liverjhep Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors 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;
Journal jhep reports (online)
Year 2020
DOI
10.1016/j.jhepr.2019.11.006
URL
Keywords
gm-csf fibrosis hcv alt, alanine aminotransferase bambi, bmp and activin membrane-bound inhibitor cd206+ macrophages daa, direct-acting antiviral dc, dendritic cell ffpe, formalin-fixed paraffin-embedded gm-csf, granulocyte-macrophage colony-stimulating factor hcc, hepatocellular carcinoma hier, heat-induced epitope retrieval hsc, hepatic stellate cells ics, intracellular cytokine staining intrahepatic macrophages lps, lipopolysaccharide lsm, liver stiffness measurement ms, multiple sclerosis nash nash, non-alcoholic steatohepatitis pbmcs, peripheral blood mononuclear cells ra, rheumatoid arthritis svr, sustained virological response tcr, t cell receptor tma, tissue microarray tnfα, tumour necrosis factor-α tsa, tyramide signal amplification anti-gm-csf neutralizing antibody momΦs, monocyte-derived macrophage-like cells t-sne, t-distributed stochastic neighbour embedding

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