Characterisation of a Novel Fc Conjugate of Macrophage Colony-stimulating Factor

Abstract

We have produced an Fc conjugate of colony-stimulating factor (CSF) 1 with an improved circulating half-life. CSF1-Fc retained its macrophage growth-promoting activity, and did not induce proinflammatory cytokines in vitro. Treatment with CSF1-Fc did not produce adverse effects in mice or pigs. The impact of CSF1-Fc was examined using the Csf1r-enhanced green fluorescent protein (EGFP) reporter gene in MacGreen mice. Administration of CSF1-Fc to mice drove extensive infiltration of all tissues by Csf1r-EGFP positive macrophages. The main consequence was hepatosplenomegaly, associated with proliferation of hepatocytes. Expression profiles of the liver indicated that infiltrating macrophages produced candidate mediators of hepatocyte proliferation including urokinase, tumor necrosis factor, and interleukin 6. CSF1-Fc also promoted osteoclastogenesis and produced pleiotropic effects on other organ systems, notably the testis, where CSF1-dependent macrophages have been implicated in homeostasis. However, it did not affect other putative CSF1 targets, notably intestine, where Paneth cell numbers and villus architecture were unchanged. CSF1 has therapeutic potential in regenerative medicine in multiple organs. We suggest that the CSF1-Fc conjugate retains this potential, and may permit daily delivery by injection rather than continuous infusion required for the core molecule.

CCR2-dependent monocyte-derived macrophages resolve inflammation and restore gut motility in postoperative ileus

“…Thus, considering that the MΦ growth factor CSF1 promotes monocyte production, recruitment, maturation and local MΦ proliferation,24 25 we assessed the effect of CSF1-Fc administration in WT and Ccr2 − / −  mice during the recovery phase after IM (figure 8). As previously reported,26 CSF1-Fc treatment increased spleen (see online supplementary figure S10A) and liver (see online supplementary figure S10B) weight in WT and Ccr2 − / −  mice. Notably, CSF1-Fc treatment restored circulating monocytes and accumulation of monocytes and MΦs into the ME of Ccr2 − / −  mice 3 days after IM (figure 8A and online supplementary figure S11).…”

An efficient method to isolate Kupffer cells eliminating endothelial cell contamination and selective bias

“…Furthermore, CD31 hi F4/80 hi CD11b lo cells did not proliferate in response to the mϕ mitogen CSF1 (Fig. H) . Thus, it would seem most likely that CD45 + F4/80 hi CD31 hi cells identified by flow cytometry represent endothelial cells with remnants of KC membranes that are largely devoid of the intracellular components of these cells.…”

An update on equine post‐operative ileus: Definitions, pathophysiology and management

“…IL-10 knockout mice fail to resolve their muscularis inflammatory response compared with wild-type mice, resulting in high mortality rates [72]. The administration of macrophage colony-stimulating factor-1 fusion protein (CSF1-Fc) [73] not only restored monocyte and MM numbers but reduced neutrophil infiltration in the muscularis, increased anti-inflammatory gene expression and improved GIT transit time following IM [55]. Additionally, while the initial leucocytic infiltrate of neutrophils and monocytes to the muscularis has been associated with SM dysfunction leading to POI, the role of monocytes/macrophages in resolution of POI has not been studied, until recently.…”