The present review summarizes recently acquired data in vivo, which support a role of CNS microglia as a source of defense cells in the CNS capable of carrying out certain immune functions autonomously. We have kept the following discussion restricted to microglial cells and have not included work on the immunological functions of astrocytes, which has been recently reviewed elsewhere (Fontana et al.: Immunological Reviews 137:3521-3527, 1987). Resting microglia are scattered uniformly throughout the CNS forming a network of potential immunoeffector cells, which can be activated by stimuli ranging from peripheral nerve injury over viral infections to direct mechanical brain trauma. The term "activated microglia" is used here to describe proliferating cells that demonstrate changes in their immunophenotype but have not undergone transformation into brain macrophages. Such a transformation can be stimulated by neuronal death but not by sublethal neuronal injury. Microglia may function as antigen-presenting cells and may thus represent the effector cell responsible for the recruitment of lymphocytes to the brain resulting in an inflammatory reaction. The recent developments in the understanding of microglial cell function may lead to a redefinition of the often cited "immune privilege" of the brain.

Functional plasticity of microglia: a review.

Brain macrophages: evaluation of microglia and their functions.

The injection of toxic lectin from Ricinus communis into the rat facial nerve resulted in suicide transport and rapid degeneration of facial motor neurons. The reaction of glial cells to neuronal death in comparison with nerve crush lesions was studied by using lectin-HRP conjugates derived from Griffonia simplicifolia for the selective staining of microglial cells at both light and electron microscopic levels. In addition, the proliferative activity of microglia was assessed by quantification of 3H-thymidine incorporation. The astrocytic response was evaluated by light microscopic immunocytochemistry for glial fibrillary acidic protein. In the degenerating facial nucleus local microglial cells responded by rapid proliferation and phagocytosis of neuronal debris. After nerve crush, no phagocytes were observed, but microglial proliferation and perineuronal satellitosis were prominent. The astrocytic expression of glial fibrillary acidic protein in response to nerve crush proceeded gradually over a period of several weeks after which it declined, contrasting with accelerated astrocytic hypertrophy and permanent glial scarring after neuronal degeneration. These results show that the expression of glial fibrillary acidic protein by fibrous astrocytes is intensified after lethal neuronal injury compared to sublethal insults. In the absence of any observations indicating participation of hematogenous elements, it is proposed that local microglial cells transform into brain macrophages.

Response of endogenous glial cells to motor neuron degeneration induced by toxic ricin.

Prominent responses that follow brain trauma include the activation of microglia, the recruitment of blood-derived macrophages, and astroglial reactivity. Based on evidence that cytokines produced by macrophages/microglia may cause astrocytes to become reactive, the aim of this study was to determine whether astroglial reactivity could be attenuated by interleukin (IL)-10, a potent inhibitor of cytokine synthesis by macrophages/microglia. Four days after the local application of IL-10 to the site of corticectomy in adult mice, the number of reactive astrocytes and their state of hypertrophy was reduced (by 60%) when compared with vehicle controls. In the majority of IL-10-treated mice, but not in any vehicle controls, the tissue in the immediate vicinity of IL-10 application contained viable but nonreactive astrocytes. The mechanism by which IL-10 attenuates astroglial reactivity is likely via the reduction of cytokine production by macrophages/microglia because, based on Mac-1 immunohistochemistry, the macrophages/microglia of IL-10 brains had a decreased activation state compared with vehicle-treated controls. Another macrophage/microglia deactivating agent, macrophage inhibitory factor, also reduced astroglial activity in vivo. Furthermore, IL-10 had no direct effect on purified astrocytes in culture, indicating that its in vivo action on astroglial reactivity is likely via indirect mechanisms. Finally, injury resulted in the substantial rise of tumor necrosis factor-α mRNA levels, and this elevation was significantly inhibited by IL-10. The ability to manipulate the extent of astrogliosis should provide a means of addressing the neurotrophic or inhibitory role of reactive astrocytes in neurological recovery.

https://www.jneurosci.org/content/jneuro/16/9/2945.full.pdf

Attenuation of Astroglial Reactivity by Interleukin-10

Vigorous expression of major histocompatibility complex (MHC) class I and class I surface glycoproteins was observed on reactive microglia but not on astrocytes in the rat brain following lesions induced by epidural kainic acid (KA) on the cerebral cortex. The monoclonal antibodies used were OX18 against MHC class I, OX6 against MHC class II, OX1 against leukocyte common antigen (LCA), and W3/13 against pan-T lymphocytes. Astrocytes were marked by antibodies to glial fibrillary acidic protein (GFA) and S100b protein. The lesion differentially affected four zones: the central area of the lesion where most cells died; the peripheral zone surrounding the lesion where selective damage occurred; projection tracts from the lesioned area; and terminal fields of damaged neurons. In nonlesioned animals, class I expression was confined to vascular endothelial cells and some small glial cells. Following KA treatment, class I-positive round cells appeared in the central zone at day 1, peaked about day 5, and then slowly declined. In the peripheral zone, class I-positive microglia were present fron day 2 on. They demonstrated classical morphology for such cells, and in some cases arranged themselves in pyramidal profiles surrounding neurons. Reactive microglia were also class I positive along tracts of damaged neurons and in the terminal areas. The reaction was reduced to control levels 16-20 weeks after lesioning although some vascular endothelial cells and a few round cells still stained positively in the cystic area, which was the remnant of the central zone. Class II antigen expression first appeared in the form of round cells in the central zone of the lesion on day 1. These peaked at 5-7 days and declined thereafter. In the peripheral zone on day 5, some positive round or ameboid cells were found intermingled with typical reactive microglia. This reaction peaked at about 1-2 weeks and decreased thereafter. Class II-positive microglia appeared in fiber tracts and in the terminal areas on day 5, peaked after 2-3 weeks, and declined thereafter. Double immunostaining for class I and II antigens showed that there were significantly fewer class II- than class I-positive cells, but the morphology of the two groups was similar. No astrocytes stained positively for either group I or group II antigen. In both the primary and secondary lesioned areas, LCA staining was observed on the surface of reactive microglia. In the primary lesions there were also LCA-positive round cells in the central zone, but these were rare in the peripheral zone and the secondary lesioned areas.(ABSTRACT TRUNCATED AT 400 WORDS)

Major histocompatibility complex antigen expression on rat microglia following epidural kainic acid lesions.

The adult dog pineal gland was studied with the electron microscope. Pineal connective tissue spaces were poorly developed and showed capillaries with nonfenestrated endothelial cells. Two cell types, pinealocytes and astrocytes, could be identified in pineal parenchyma. Dog pinealocytes showed microtubules, centrioles, occasional cilia, and well-developed Golgi complexes. These cells showed thin processes with bulbous endings packed with vesicles. Astrocytes were characterized by the presence of numerous filaments. Their processes finished forming a glial layer bordering connective tissue spaces. The presence of myelinated and unmyelinated nerve fibers was also described.

Ultrastructure of the pineal gland in the adult dog.

The nature of phagocytes appearing in lesions of the central nervous system is strongly debated with a tendency to assess an exclusively hematogenous origin. We studied the origin of phagocytes appearing in a stab wound in the rat brain. Histochemical stains for acid phosphatase and peroxidase, and silver impregnation techniques were used for our study. The results obtained showed the existence of two macrophage types: endogenous microghocytes and exogenous monocytes.

E. Garcia-Mauriño

Papers

Ultrastructure of the pineal gland in the adult dog.

Nature of Macrophages in Rat Brain