Pleiotropic effects of extended blockade of CSF1R signaling in adult mice.

Kristin A Sauter,Lee B Smith,Neil A Mabbott,Anuj Sehgal,Barry M Bradford,Clare Pridans,Lindsey Moffat,Philippa M Beard,Sobia Raza,David A Hume,Yi Ting Tsai,Deborah J Gow

doi:10.1189/jlb.2a0114-006r

Kristin A Sauter, Lee B Smith + Show 10 more

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https://doi.org/10.1189/jlb.2a0114-006r

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Abstract

We investigated the role of CSF1R signaling in adult mice using prolonged treatment with anti-CSF1R antibody. Mutation of the CSF1 gene in the op/op mouse produces numerous developmental abnormalities. Mutation of the CSF1R has an even more penetrant phenotype, including perinatal lethality, because of the existence of a second ligand, IL-34. These effects on development provide limited insight into functions of CSF1R signaling in adult homeostasis. The carcass weight and weight of several organs (spleen, kidney, and liver) were reduced in the treated mice, but overall body weight gain was increased. Despite the complete loss of Kupffer cells, there was no effect on liver gene expression. The treatment ablated OCL, increased bone density and trabecular volume, and prevented the decline in bone mass seen in female mice with age. The op/op mouse has a deficiency in pancreatic β cells and in Paneth cells in the gut wall. Only the latter was reproduced by the antibody treatment and was associated with increased goblet cell number but no change in villus architecture. Male op/op mice are infertile as a result of testosterone insufficiency. Anti-CSF1R treatment ablated interstitial macrophages in the testis, but there was no sustained effect on testosterone or LH. The results indicate an ongoing requirement for CSF1R signaling in macrophage and OCL homeostasis but indicate that most effects of CSF1 and CSF1R mutations are due to effects on development.

Highlights

CSF1 controls the proliferation, differentiation, maturation, and survival of cells of the mononuclear phagocyte system [1,2,3,4]
Expression of Csf1r mRNA is myeloid-restricted in adult animals, and a Csf1r-EGFP reporter gene provides a convenient marker for macrophage-lineage cells in transgenic mice [5]
We have shown elsewhere that CSF1-dependent macrophages are a significant source of IGF1 in the postnatal period [18]

Summary

Introduction

CSF1 controls the proliferation, differentiation, maturation, and survival of cells of the mononuclear phagocyte system [1,2,3,4]. The effects of CSF1 are mediated through the CSF1R, a protein tyrosine kinase receptor. Expression of Csf1r mRNA is myeloid-restricted in adult animals, and a Csf1r-EGFP reporter gene provides a convenient marker for macrophage-lineage cells in transgenic mice [5]. A natural mutation of the Csf gene in mice (op/op) produces a reduction in macrophage numbers in most tissues of the body, accompanied by severe growth retardation, osteopetrosis, and deficiencies in sensory, reproductive, and other endocrine systems [3, 4]. A null mutation of Csf1r produces even more penetrant phenotypes, including a significant postnatal mortality [6]. A second ligand for CSF1R, IL-34, provides an explanation for the greater impact of receptor depletion. IL-34 appears to be required for the generation of specific macrophage populations, notably microglia in the brain and epidermal Langerhans cells [7, 8]

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