Administration of human macrophage colony-stimulating factor-mFc fusion protein increases macrophage phagocytic capacity and stimulates liver regeneration in mice.

backgroundAcute and chronic liver diseases are rising contributors of the worldwide healthcare burden. Inflammation plays a key role in progression of both acute and chronic disease, and effective treatments are limited. Macrophages, a diverse population of professional phagocytes, are required for the timely resolution of tissue injury and are an emerging target to treat acute and chronic liver disease. Colony stimulating factor 1 (CSF1), promotes differentiation and survival of macrophages, which are essential in epithelial regeneration, but the CSF1 protein is rapidly eliminated in vivo. We therefore fused human CSF1 genetically to a modified mouse IgG2a Fc region and transiently expressed this in HEK293-6E cells. The protein was purified from culture supernatant to obtain > 97% monomeric purity, suitable for in vivo testing.

resultsThe nascent hCSF1-Fc fusion proteins were evaluated in vitro and in murine models of health and liver disease. hCSF1-mFc is pharmacologically active in healthy mice, resulting in increases in liver and spleen mass closely reflecting changes in tissue macrophage content. In an acetaminophen-induced acute liver injury model, hCSF1-mFc treatment increased hepatic macrophage accumulation at necrotic sites, reduced serum ALT activity, and serum IL-1β levels, and restored white blood cell counts within 72 h. Furthermore, hCSF1-mFc treatment also increased hepatic macrophage numbers in a carbon tetrachloride (CCl

conclusionThis report demonstrates that hCSF1-mFc treatment increases liver macrophage populations, improves phagocytic capacity, and stimulates hepatocyte proliferation in experimental liver disease models. hCSF1-based fusion protein therapy might represent a novel immune-based strategy to treat acute and chronic liver disease in the clinic. CLINICAL TRIAL NUMBER: Not applicable.