Microglia: a sensor to threats in the nervous system?

The parenchymal microglia are now believed to settle the CNS antenatally, being derived from a bone marrow precursor cell. Based on developmental and pathophysiological studies, at least four different types of parenchymal microglia can be distinguished: (i) the amoeboid microglia which are mainly found perinatally in white matter areas, such as the corpus callosum, i.e. the so-called "fountains of microglia", (ii) the ramified, resting microglia in the adult CNS, (iii) the activated, non-phagocytic microglia found in areas of secondary reaction due to nerve transection and (iv) the phagocytic microglia, found in areas of trauma, infection or neuronal necrosis. In addition, there are perivascular cells enclosed in the basal lamina which have a high turnover with a bone marrow precursor pool. While the function of resting microglia is still largely unknown, it is clear from observations in neuropathology that microglia are among the first cell types in the brain to respond to injuries. Their reaction pattern to injury has been termed a graded response, since the transformation of resting cells into phagocytes is under strict control in vivo. Microglial activation is a key cellular response in many infectious, inflammatory, traumatic, neoplastic, ischaemic and degenerative conditions in the CNS. In HIV encephalitis, the microglial involvement is striking, and approximately 25% of microglia contain viral DNA or RNA. Based on natural homing mechanisms with bone marrow precursor cells, HIV-infected monocytes/macrophages may home at an early stage to the CNS perivascular space and eventually spread the infection to resident microglia in the CNS which may be difficult to reach by pharmacological intervention. Further understanding of the mechanisms regulating microglial proliferation and activation in vivo may help to develop therapies targeting the potentially harmful microglial response in the injured CNS.