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

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.

• Authors: Alfonso Tan-Garcia, Fritz Lai, Joe Poh Sheng Yeong, Sergio E Irac, Pei Y Ng, Rasha Msallam, Jeffrey Chun Tatt Lim, Lu-En Wai, Christine Y L Tham, Su P Choo, Tony Lim, Dan Y Young, Roberta D'Ambrosio, Elisabetta Degasperi, Riccardo Perbellini, Evan Newell, Nina Le Bert, Florent Ginhoux, Antonio Bertoletti, Qingfeng Chen, Charles-Antoine Dutertre
• Journal: JHEP reports : innovation in hepatology (JHEP Rep) Vol. 2 Issue 1 Pg. 100062 (Feb 2020) ISSN: 2589-5559 [Electronic] Netherlands
• PMID: 32039403 (Publication Type: Journal Article)
• Copyright: © 2019 The Author(s).