Therapeutic potential of macrophage colony-stimulating factor (CSF1) in chronic liver disease

Keshvari, S.; Genz, B.; Teakle, N.; Caruso, M.; Cestari, M. F.; Patkar, O. L.; Tse, B. W.; Sokolowski, K. A.; Ebersbach, H.; Jascur, J.; MacDonald, K. P.; Miller, G.; Ramm, G. A.; Pettit, A. R.; Clouston, A. D.; Powell, E. E.; Hume, D. A.; Irvine, K. M.

doi:10.1101/2021.11.07.467663

bioRxiv · 10.1101/2021.11.07.467663

Therapeutic potential of macrophage colony-stimulating factor (CSF1) in chronic liver disease

Keshvari, S.·Genz, B.·Teakle, N.·Caruso, M.·Cestari, M. F.·Patkar, O. L.·Tse, B. W.·Sokolowski, K. A.·Ebersbach, H.·Jascur, J.·MacDonald, K. P.·Miller, G.·Ramm, G. A.·Pettit, A. R.·Clouston, A. D.·Powell, E. E.·Hume, D. A.·Irvine, K. M.

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Abstract

Resident and recruited macrophages control the development and proliferation of the liver. We showed previously in multiple species that treatment with a macrophage colony stimulating factor (CSF1)-Fc fusion protein initiated hepatocyte proliferation and promoted repair in models of acute hepatic injury in mice. Here we investigated the impact of CSF1-Fc on resolution of advanced fibrosis and liver regeneration, utilizing a non-resolving toxin-induced model of chronic liver injury and fibrosis in C57BL/6J mice. Co-administration of CSF1-Fc with exposure to thioacetamide (TAA) exacerbated inflammation consistent with monocyte contributions to initiation of pathology. After removal of TAA, either acute or chronic CSF1-Fc treatment promoted liver growth, prevented progression and promoted resolution of fibrosis. Acute CSF1-Fc treatment was also anti-fibrotic and pro-regenerative in a model of partial hepatectomy in mice with established fibrosis. The beneficial impacts of CSF1-Fc treatment were associated with monocyte-macrophage recruitment and increased expression of remodeling enzymes and growth factors. These studies indicate that CSF1-dependent macrophages contribute to both initiation and resolution of fibrotic injury and that CSF1-Fc has therapeutic potential in human liver disease. Summary statementMacrophages contribute to both progression and resolution of chronic tissue injury and fibrogenesis. Administration of a macrophage growth factor promoted liver regeneration and resolution of advanced liver fibrosis in mice.

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Keshvari, S., Genz, B., Teakle, N., Caruso, M., Cestari, M. F., Patkar, O. L., Tse, B. W., Sokolowski, K. A., Ebersbach, H., Jascur, J., MacDonald, K. P., Miller, G., Ramm, G. A., Pettit, A. R., Clouston, A. D., Powell, E. E., Hume, D. A., Irvine, K. M.. 2021-11-08. Therapeutic potential of macrophage colony-stimulating factor (CSF1) in chronic liver disease. https://doi.org/10.1101/2021.11.07.467663

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