Basic Properties Of Microglia A Microglia in the Normal CNS

The CNS is composed of neurons and a nonneuronal population of cells, designated glia, that includes astrocytes, oligodendrocytes, and microglia. del Rio Hortega discovered microglia in 1919 when he developed the silver carbonate methology. He identified process-bearing cells in the CNS parenchyma and named these cells microglia. Microglia contribute to about 10% of the total glial cell population in the CNS of adults. In the 1960s, the existence of ramified microglia as a distinct glial population was further confirmed by electron microscopy showing lack of intracellular intermediate filaments and intercellular gap junctions that are typical ultrastructural features of astrocytes. In contrast to oligodendrocytes, the principal myelin-forming cells of the CNS, microglia do not entertain myelin sheaths. Microglia are present in all parts of the brain and spinal cord (Fig. 1) but are

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Figure 1 Parenchymal microglia in the rat brain. Sections of the sensomotor cerebral cortex (A), hippocampus (B-D), and cortical white matter (E, F) stained immunocytochemically with antibodies against the complement receptor-3 (CR-3) (A, B, E, F) and against keratan sulfate proteoglycans (KSPG) (C, D) to identify microglia. Note the widespread distribution of microglia in the cortex (A) and their typical ramified morphology (D). Microglia show a more longitidinal orientationin white matter tracts (E,F). More microglia express CR-3 (B) than KSPG (C). Scale bars = 200 mm in A, 80 mm in and B and C, 20 mm in D and F, and 40 mm in E.

Figure 1 Parenchymal microglia in the rat brain. Sections of the sensomotor cerebral cortex (A), hippocampus (B-D), and cortical white matter (E, F) stained immunocytochemically with antibodies against the complement receptor-3 (CR-3) (A, B, E, F) and against keratan sulfate proteoglycans (KSPG) (C, D) to identify microglia. Note the widespread distribution of microglia in the cortex (A) and their typical ramified morphology (D). Microglia show a more longitidinal orientationin white matter tracts (E,F). More microglia express CR-3 (B) than KSPG (C). Scale bars = 200 mm in A, 80 mm in and B and C, 20 mm in D and F, and 40 mm in E.

not uniformly distributed. Microglia are located in close vicinity to neurons in the gray matter (Figs. 1A-1C) and between fiber tracts in the white matter of the CNS (Figs. 1E and 1F). More microglia are found in gray than in white matter. Microglia vary in morphology depending on their location. Longitudinally branched cells are found in fiber tracts (Figs. 1E and 1F). They possess long processes that are usually aligned parallel to the longitudinal axis of the nerve fibers. Radially branched cells are found throughout the gray matter (Fig. 1D). During normal aging microglia undergo morphological changes. Although in newborn brain few ramified microglia can be detected, they increase in number during postnatal development and are abundant in the middle-aged human brain. In the aged brain microglia change morphology again and show signs of activation, with enlarged longitudinally arranged processes.

Today, microglia can unequivocally be distinguished from other resident, nonneuronal cells in the CNS by immunocytochemistry. Resting microglia constitutively express the complement type-3 receptor (CR3; CD11b/CD18 complex) (Figs. 1A, 1B, and 1E), Fc receptors for binding of immunoglobulins, and galactose-containing glycoconjugates that bind isolec-tin B4 from Griffonia simplicifolia seeds. However, these antigens are not specific for microglia. Hemato-genous macrophages that invade the CNS under certain pathological conditions also express CR3, Fc receptors, and the lectin binding site. Currently, the only antigen to our knowledge that is not shared between microglia and macrophages is a keratan sulfate proteoglycan epitope (KSPG) detected by monoclonal antibody 5D4 (Figs. 1C and 1D), which, underlies modification during immune-mediated processes in the CNS. In the gray and white matter of the normal rat CNS, a subpopulation of rat parenchymal microglia constitutively express KSPG.

Resting microglia generally express low to absent levels of major histocompatibility complex (MHC) class II molecules. These molecules are important for immune reactions. Already within a given species there are fundamental differences in the expression of microglial surface molecules. Whereas in the rat constitutive MHC class II expression of ramified microglia can be detected in Brown Norway and Dark Agouti strains, it is virtually absent in Lewis and Fischer 344 rats. Interestingly, constitutive MHC class II expression is inversely related to KSPG expression. These findings suggest a significant impact of genetic factors on the molecular differentiation of resident microglia in the normal CNS that are not yet elucidated.

Microglia respond to a variety of functional and lesional disturbances in the CNS. This response is accompanied by characteristic morphological and molecular signs of activation. Activated microglia retract processes followed by rounding of the cell body, particularly in conditions in which microglia finally act as phagocytes. This is associated with increased levels of CR3 expression on the surface. As a relatively early sign of microglial activation, MHC class I and II antigens are upregulated on the cellular surface, which enables microglia to interact directly with T cells. Except in mice, activated microglia express CD4 antigens, which are accessory molecules of T helper lymphocytes. Upon further transition into phagocytes, microglia develop intracellular phagolyso-somes that can be visualized by immunocytochemistry. All these molecules indicative of microglial activation are also present on hematogenous monocytes/macro-phages. This makes a distinction between the relative contribution of activated local microglia and that of invading macrophages from the blood in CNS disorders, in which both cell types are involved, difficult.

A subset of microglia, the perivascular microglia (which have also been termed perivascular cells), can be distinguished by their unique association with vessels and by immunocytochemistry using mab ED2 in the rat (Figs. 2A and 2C). These cells are spindle shaped and located around blood vessels. Perivascular microglia constitutively express the immune activation markers CD4 and MHC class II molecules (Figs. 2B, 2D, and 2E).

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