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.
Colony-stimulating factor 1 (CSF1) controls the growth and differentiation of macrophages.CSF1R signaling has been implicated in the maintenance of the intestinal stem cell niche and differentiation of Paneth cells, but evidence of expression of CSF1R within the crypt is equivocal. Here we show that CSF1R-dependent macrophages influence intestinal epithelial differentiation and homeostasis. In the intestinal lamina propria CSF1R mRNA expression is restricted to macrophages which are intimately associated with the crypt epithelium, and is undetectable in Paneth cells. Macrophage ablation following CSF1R blockade affects Paneth cell differentiation and leads to a reduction of Lgr5+ intestinal stem cells. The disturbances to the crypt caused by macrophage depletion adversely affect the subsequent differentiation of intestinal epithelial cell lineages. Goblet cell density is enhanced, whereas the development of M cells in Peyer’s patches is impeded. We suggest that modification of the phenotype or abundance of macrophages in the gut wall alters the development of the intestinal epithelium and the ability to sample gut antigens.
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