Liver fibrosis and CD206+ macrophage accumulation are suppressed by anti-GM-CSF therapy Tan-Garcia, Alfonso et al. JHEP Reports, Volume 2, Issue 1, 100062
Background & Aims: Chronic liver inflammation leads to fibrosis and cirrhosis and is associated with an accumulation of intrahepatic TNFa-secreting CD206+ macrophages, which may participate in maintaining chronic liver disease in a GM-CSFdependent 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-viralrelated 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 TNFa 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 TNFa-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 HBVinfected 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.
This work was supported by the following grants - Translational and Clinical Research grant (NMRC/TCR/014-NUHS/2015) from the National Medical Research Council (NMRC), National Research Foundation Fellowship Singapore NRF-NRFF2017-03 and the Basic research New Investigator grant (NMRC/BNIG/2026/2014) from NMRC.