Circulating monocytic cells infiltrate layers of anterograde axonal degeneration where they transform into microglia

In this study, we demonstrate the infiltration of blood-derived monocytic cells and their morphologic transformation into microglia in zones of acute, anterograde ( Wallerian) axonal degeneration induced by entorhinal cortex lesion (ECL). ECL was performed in mice which had received green fluorescent protein (GFP)-transduced bone marrow grafts allowing identification of blood-derived elements within the brain. While in the unlesioned hemisphere GFP(+) cells were restricted to perivascular and leptomeningeal sites, many round fluorescent cells appeared in hippocampal zones of axonal degeneration at 24 h post lesion (hpl). Within 72 hpl, these GFP(+) cells acquired ramified, microglia-like morphologies, which persisted for at least 7 days post ECL. Differentiation of GFP(+) cells into glial fibrillary acidic protein (GFAP)(+) astrocytes was never observed. To exclude that this recruitment is an artifact of irradiation or bone marrow transplantation, the fluorescent cell tracker 6-carboxylfluorescein diacetate (CFDA) was injected into spleens of normal mice 1 day before ECL. Again, fluorescent cells appeared at the lesion site and along the layers of axonal degeneration at 48 hpl and CFDA(+)/ MAC-1(+), cells exhibited amoeboid and ramified morphologies. Thus, blood-derived cells infiltrate not only the site of mechanical lesion, but also the layers of anterograde axonal degeneration, where they readily transform into microglia-like elements. A role for infiltrating leukocytes in facilitating or modulating postlesional plasticity, e.g., by phagocytosis of growth-inhibiting myelin should now be considered. Moreover, monocytic cells may serve as vehicles to transport therapeutic substances such as neurotrophic factors or caspase inhibitors to zones of axonal degeneration.