Microglia

Unlike Müller cells and astrocytes, which are derived from the neuroec-toderm, the microglia have a mesenchymal origin similar to endothelial cells and pericytes (Ling, 1981). Microglia are typically small cells with a thin cytoplasmic rim surrounding the nucleus, and short branching processes that often encircle retinal capillaries (Wolter, 1959; Vrabec, 1970); some microglial cells extend fine processes to, or are located within the plexiform layers (Fig. 1.20; cf. Provis et al., 1995; Boycott and Hopkins, 1981; Hume et al., 1983). Their dense cytoplasm contains Golgi complexes and prominent wide cisternae of rough endoplasmic reticulum (Hogan et al., 1971) but few cytoskeletal elements. Although expression ofvimentin in CNS microglia has been reported following injury (Graeber et al., 1988), this feature has not yet been studied in the vertebrate retina. Differences in antigenic properties indicate that the retinal microglia consist of a heterogeneous population of cells (Provis et al., 1995), but it is not known whether the various subtypes differ functionally.

The distribution of microglia appears to be age dependent (Ling, 1982), and it has been suggested that changes in their distribution may reflect the pattern of cell death at various stages of retinal development (Hume et al., 1983). In rat retina, microglia are detected as early as embryonic day 12, precursor cells having entered the retina from the blood stream probably via the hyaloid circulation (cf. Ling, 1981; Ashwell et al., 1989).

Figure 1.20. Flat mounts of normal human retina showing microglia labeled with antibodies directed against MHC-II antigens and the leukocyte common antigen, CD45. A. CD45 immu-noreactive microglia within the inner plexiform layer of the retina illustrates their typical ramified morphology. Scale bar = 100 ^m. B. Perivascular microglial cells immunoreactive to MHC-II antibody are closely apposed to a medium caliber vessel of the inner retina. Scale bar = 10 ^m (Provis et al., 1995). (Copyright 1995 Wiley-Liss, a subsidiary ofJohn Wiley & Sons, Inc., reprinted with permission.)

However, the notion that the initial entry of microglia into the retina is triggered by the developmentally determined onset of neuronal death (Hume et al., 1983) has not been borne out in studies showing that their appearance in embryonic retina precedes by at least five days the wave of ganglion cell death (Ashwell et al., 1989).

The microglia are usually seen in association with the retinal vasculature (Fig. 1.20). In the monkey (Mucaca mulutta) retina they are found in all layers from the margin of the inner retina to the outer plexiform layer, where they are closely apposed to the outermost retinal capillaries (Vrabec, 1970). A similar distribution was also seen in the rabbit retina (Vrabec, 1970), but their presence in the plexiform layers of the rabbit cannot be linked to vascular sites because capillaries do not enter the neural retina of this species. These observations have been confirmed and extended by means of light- and electron-microscopic studies of Golgi-impregnated retinas from other mammalian species, e.g., cat, squirrel monkey, and rabbit (Boycott and Hopkins, 1981). However, the distribution of microglia in the mature rat retina appears to be somewhat different. Through the use of peroxidase-conjugated lectins that label selectively the microglia and endo-thelial cells, it was possible to trace the development of microglia from embryonic to early postnatal stages (Ashwell et al., 1989). In embryonic retina, the microglial cells were indeed seen throughout the thickness of the retina, but as the retina differentiated and a laminar structure began to form, they were progressively confined to the inner half of the retina. It is not yet known whether differences in the retinal distribution of microglia in rat and that reported for rabbit and primates are indicative of species differences, or are due to the different methods and criteria for identifying these cells.

There is general agreement that microglia are analogous to the histio-cytes of the CNS, and that they exhibit similar phagocytic properties in response to injury. In the retina, resident microglia proliferate and display "ameboid" motion to engulf and phagocytose the debris of dying cells during the period of neuronal death that accompanies normal retinal development (Potts et al., 1982; Ling, 1982; Hume et al., 1983; Ashwell et al., 1989). Presumably, these wandering scavengers then deliver the lipids of the destroyed neurons to the vascular system for disposal (Wolter, 1959; Jaco-biec, 1982). If retinal astrocytes behave similarly to microglia in other parts of the nervous system, it is likely that their phagocytic activity will be stimulated also in response to exogenously induced forms of neuronal injury (cf. Graeber et al., 1988; Streit et al., 1988). The ability of microglia to produce growth factors, e.g., the cytokine interleukin-1 (Giulian et al., 1986), has been taken to suggest that these cells may play a role in the inflammatory response to nerve damage (Brenneman et al., 1992).

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