Date Published: March 1, 2018
Publisher: American Physiological Society
Author(s): Clare Pridans, Kristin A. Sauter, Katharine M. Irvine, Gemma M. Davis, Lucas Lefevre, Anna Raper, Rocio Rojo, Ajit J. Nirmal, Philippa Beard, Michael Cheeseman, David A. Hume.
Signaling via the colony-stimulating factor 1 receptor (CSF1R) controls the survival, differentiation, and proliferation of macrophages. Mutations in CSF1 or CSF1R in mice and rats have pleiotropic effects on postnatal somatic growth. We tested the possible application of pig CSF1-Fc fusion protein as a therapy for low birth weight (LBW) at term, using a model based on maternal dexamethasone treatment in rats. Neonatal CSF1-Fc treatment did not alter somatic growth and did not increase the blood monocyte count. Instead, there was a substantial increase in the size of liver in both control and LBW rats, and the treatment greatly exacerbated lipid droplet accumulation seen in the dexamethasone LBW model. These effects were reversed upon cessation of treatment. Transcriptional profiling of the livers supported histochemical evidence of a large increase in macrophages with a resident Kupffer cell phenotype and revealed increased expression of many genes implicated in lipid droplet formation. There was no further increase in hepatocyte proliferation over the already high rates in neonatal liver. In conclusion, treatment of neonatal rats with CSF1-Fc caused an increase in liver size and hepatic lipid accumulation, due to Kupffer cell expansion and/or activation rather than hepatocyte proliferation. Increased liver macrophage numbers and expression of endocytic receptors could mitigate defective clearance functions in neonates.
Signals initiated following binding of macrophage colony-stimulating factor 1 (CSF1) or IL-34 to a shared receptor (CSF1R) control the survival, differentiation, and proliferation of cells of the mononuclear phagocyte lineage (6, 21, 24). Mutation of CSF1 in rats or mice produces a global deficiency of macrophage numbers in most tissues, whereas IL-34 appears to be required more specifically for macrophages of the brain (microglia) and skin (Langerhans cells) (55). Mutation of the receptor CSF1R, which ablates the response to both ligands, has a more penetrant phenotype in mice (8) and rats (C. Pridans, A. Raper, G. M. Davis, J. Alves, K. A. Sauter, L. Lefevre, T. Regan, S. Meek, L. Sutherland, A. J. Thomson, S. Clohisey, R. Rojo, Z. M. Lisowski, R. Wallace, K. Grabert, K. R. Upton, Y. T. Tsai, D. Brown, L. B. Smith, K. M. Summers, N. A. Mabbott, P. Piccardo, M. T. Cheeseman, T. Burdon, D. A. Hume, unpublished observations). The requirement for continuous CSF1R signaling is retained in adult mice, in that treatment with an anti-CSF1R antibody depletes tissue macrophages from the majority of organs (26). However, the availability of CSF1R ligands in vivo is not saturating. Administration of recombinant human CSF1 to mice expanded the circulating blood monocyte and tissue macrophage populations (22). These studies subsequently led to confirmation of biological efficacy in human patients (reviewed in Ref. 21). The circulating CSF1 concentration is controlled by CSF1R-mediated endocytic clearance by macrophages of the liver and spleen (3), providing a homeostatic loop in which tissue macrophages control monocyte production from the bone marrow (BM) (24). Accordingly, anti-CSF1R treatment or mutation of the receptor increases circulating CSF1 concentration (8, 26). Macrophages throughout the body occupy defined niches or territories (17), and the local availability of CSF1 in tissues may be one determinant of the size/boundary of those territories and local self-renewal of macrophages (24).
Concentrations of CSF1 were found to be higher in fetal than in maternal blood throughout mouse gestation and to peak around the time of birth, at which time there was also a peak of CSF1 protein in the liver (41). In humans, CSF1 is also elevated in the embryonic circulation relative to the maternal, and there was a two- to threefold increase in the first few days after a full-term birth (40). In the current study, we examined the possible roles of that increase in available CSF1 by administering an exogenous source for the first 5 days of life in rats.
This work was funded by the Medical Research Council Grant MR/M019969/1. The Roslin Institute also receives Institute Strategic grant funding from the Biotechnology and Biological Sciences Research Council.
No conflicts of interest, financial or otherwise, are declared by the authors.
C.P. and D.A.H. conceived and designed research; C.P., K.A.S., G.M.D., L.L., A.R., and R.R. performed experiments; C.P., K.M.I., A.J.N., and D.A.H. analyzed data; C.P., K.M.I., P.B., M.C., and D.A.H. interpreted results of experiments; C.P. and K.M.I. prepared figures; C.P. and D.A.H. drafted manuscript; C.P., K.M.I., A.J.N., and D.A.H. edited and revised manuscript; C.P., K.M.I., and D.A.H. approved final version of manuscript.