Inhibition of Posttraumatic Microglial Proliferation in a Genetic Model of Macrophage Colony‐Stimulating Factor Deficiency in the Mouse

Abstract

Activation and proliferation of microglia are common cellular hallmarks in many different pathological processes of the central nervous system. Although a number of colony-stimulating factors enhance microglial proliferation in vitro, little is known about the endogenous mitogens. In the present study we show a strong and selective inhibition of microglial proliferation in the facial nucleus of osteopetrotic (op/op) mice, with a genetic deficiency in biologically active macrophage colony-stimulating factor (MCSF). Posttraumatic activation of adjacent axotomized neurons and reactive astrocytes was not affected, emphasizing the specificity of MCSF as a microglial growth factor.

The microglial phagocytic role with specific plaque types in the Alzheimer disease brain

“…Finally, ongoing experiments in which CNS microglial activation has been genetically suppressed in APP transgenics by the op/op mutation [52] which has fewer microglia appear to result in more rather than less amyloid (unpublished results, GMC), again supporting the concept that microglia play a role in normal amyloid clearance while suppression of microglia activation or clearance leads to more rather than less amyloid.…”

Entry, dispersion and differentiation of microglia in the developing central nervous system

“…The influence of these factors on microglial cell proliferation has been shown in vitro but there are no experimental studies that demonstrate it in vivo . In addition, in op/op mice, which are deficient in CSF-1, the number of microglia in the CNS is not affected (Berezovskaya et al 1995) suggesting that CSF-1 has no influence on microglial proliferation during in vivo development, despite the fact that CSF-1 deficiency inhibits the normal in vitro development of microglia (Blevins & Fedoroff 1995) and the proliferation of activated microglia after axotomy in adulthood (Raivich et al 1994). On the other hand, other factors such as the pigment epithelium-derived factor (Sugita et al 1997), cer-tain corticosteroids (Ganter et al 1992), and adrenergic agonists (Fujita et al 1998) have been shown to inhibit proliferation of microglia in vitro.…”

Endogenous Transforming Growth Factor β1 Suppresses Inflammation and Promotes Survival in Adult CNS

“…After injury, activated microglia rapidly proliferate (Raivich et al, 1994), migrate to the affected site, and adhere to the injured neurons , displacing the neurite terminals in a process known as synaptic stripping (Blinzinger and Kreutzberg, 1968;Trapp et al, 2007). After synaptic stripping, the microglia gradually migrate into the nearby parenchyma, where they appear to downregulate their cellular markers and decrease in number .…”

“…Parallel to the microglial activation, reactive astrocytes show a rapid increase in signaling receptors, neurotrophins, growth factors, and extracellular matrix proteins, all of which play an important regulatory role in the repair and regeneration process (Eddleston and Mucke, 1993). Although several key molecules like MCSF (macrophage colonystimulating factor) and IL-6 (interleukin-6) have been identified for their role in the activation of microglia and astrocytes after neural injury (Raivich et al, 1994;Klein et al, 1997;Galiano et al, 2001;Kalla et al, 2001), little is known about the endogenous signals involved in the downregulation of these glial cells after injury, as well as their persistently downregulated state in the uninjured CNS. One candidate molecule here is the immunosuppressive cytokine transforming growth factor ␤ 1 (TGF␤1).…”