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 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 and 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 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.

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.