Effects of macrophage‐colony‐stimulating factor deficiency on the maturation of microglia and brain macrophages and on their expression of scavenger receptor

Abstract

Macrophage-colony-stimulating factor (M-CSF) regulates the survival, proliferation and differentiation of the mononuclear phagocyte lineage. Osteopetrotic (op/op) mice defective in producing functional M-CSF were used in order to investigate the role of M-CSF on the development of microglia and brain macrophages and the expression of scavenger receptor (SR). Adult op/op and littermate mice at 10-47 weeks of age were investigated by immunohistochemistry with a panel of monoclonal antibodies (F4/80, Mac-1, anti-major histocompatibility complex (MHC) class II and anti-SR), electron microscopy and reverse transcriptase-polymerase chain reaction (RT-PCR). Microglia were weakly immunolabeled with F4/80 and Mac-1 in op/op and littermate mice, but the number of microglia in op/op mice was reduced in the cerebrum, cerebellum and brainstem compared with that of normal littermates. The numbers of Mac-1-positive microglia in op/op mice was 39% (pons) and 30% (cerebellar cortex) lower than that in normal littermates (P<0.05). In addition, the microglia cell processes in op/op mice were often shorter than those in control mice. In op/op and littermate mice, both MHC class II and SR were present in perivascular cells and macrophages of the leptomeninx and choroid plexus. Ultrastructurally, perivascular cells appeared to be immature, since their cytoplasm was narrow and contained few inclusion bodies compared with those of control mice. Reverse transcriptase-polymerase chain reaction showed a weak expression for SR mRNA in the brains of op/op mice as well as littermate mice. These results indicate that microglia are partly dependent on M-CSF for their proliferation and differentiation and that M-CSF has no significant effect on the expression of SR in the physiological brain. The study also suggests that M-CSF affects the maturation of perivascular cells at the ultrastructural level.

Apolipoprotein E Modulates Clearance of Apoptotic Bodies In Vitro and In Vivo, Resulting in a Systemic Proinflammatory State in Apolipoprotein E-Deficient Mice

“…It was not possible to use the same Ab markers to characterize the brain tissue macrophage population (the microglia) because they only stained weakly with the F4/80 mAb, consistent with previous findings (42). However, an Ab against MHC class II (which only stains a subset of the F4/80 ϩ cells in liver and lung) stained the microglia as previously described (42).…”

“…However, an Ab against MHC class II (which only stains a subset of the F4/80 ϩ cells in liver and lung) stained the microglia as previously described (42). ApoE deficiency increased the number of MHC class II ϩ cells in the brain (Fig.…”

A Requirement for Microglial TLR4 in Leukocyte Recruitment into Brain in Response to Lipopolysaccharide

“…To date, a microglia-deficient mouse does not exist, and the macrophage-deficient op/op mice have only a 30% reduction in microglia (14). In the last few years, a novel microglial inhibitor was identified.…”

Modeling CNS microglia: the quest to identify predictive models

“…As yet, there is no spontaneous viable mammalian mutant that lacks CNS-resident microglia. Even the op/op mouse, a spontaneous deletion mutation resulting in loss of CSF-1, a necessary macrophage growth factor, show only a modest reduction in CNS-microglia [21,22]. Interestingly, the reduction is only detectable in selected brain regions and is much less than that the reduction observed in other peripheral macrophage populations.…”