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Background <p>Acute 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 &gt; 97% monomeric purity, suitable for in vivo testing.</p> Results <p>The 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&#xa0;h. Furthermore, hCSF1-mFc treatment also increased hepatic macrophage numbers in a carbon tetrachloride (CCl<sub>4</sub>)-induced liver fibrosis model corresponding with a striking 3.5-fold increased uptake of a soluble phagocytic label, indicating improved hepatic clearance capacity. hCSF1-mFc was also tested in a model of acute on chronic liver injury, which included a bolus delivery of proinflammatory <i>E. coli</i>-coated bioparticles to pre-existing fibrosis. Here, hCSF1-mFc treatment restored body weight, induced hepatomegaly, and reduced several plasma pro-inflammatory cytokines, suggesting reduction of systemic inflammation. Finally, immunofluorescence staining showed hCSF1-mFc treatment induced significant hepatocyte proliferation in healthy and all liver disease models.</p> Conclusion <p>This 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.</p> Clinical trial number <p>Not applicable.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月25日

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  • Philip J. Starkey Lewis,
  • Jennifer A. Cartwright,
  • Lara Campana,
  • Birgit U. Baumgarten,
  • Hilmar Ebersbach,
  • Marie-Gabrielle Ludwig,
  • Gregory Marszalek,
  • Benjamin Stutchfield,
  • Rhona Aird,
  • Tak-Yung Man,
  • Eoghan O’Duibhir,
  • Klaus Seuwen,
  • Stuart J. Forbes

摘要

Background

Acute 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.

Results

The 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 (CCl4)-induced liver fibrosis model corresponding with a striking 3.5-fold increased uptake of a soluble phagocytic label, indicating improved hepatic clearance capacity. hCSF1-mFc was also tested in a model of acute on chronic liver injury, which included a bolus delivery of proinflammatory E. coli-coated bioparticles to pre-existing fibrosis. Here, hCSF1-mFc treatment restored body weight, induced hepatomegaly, and reduced several plasma pro-inflammatory cytokines, suggesting reduction of systemic inflammation. Finally, immunofluorescence staining showed hCSF1-mFc treatment induced significant hepatocyte proliferation in healthy and all liver disease models.

Conclusion

This 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.