Perivascular location and phenotypic heterogeneity of microglial cells in the rat brain.
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Animals↗
Biomedical subjects
M B Graeber
Publications and source records attributed to M B Graeber.
Immunoelectron microscopic localization of laminin in normal and regenerating mouse sciatic nerve.
Laminin, the major non-collagenous protein of basement membranes, has been shown to be a potent stimulator of neurite outgrowth, to potentiate neuronal survival and to stimulate Schwann cell division in vitro. The aim of the present study was to determine the ultrastructural localization of laminin in the mouse sciatic nerve during development and regeneration in order to elucidate whether laminin might also evoke similar effects in vivo. For this purpose polyclonal antibodies against laminin were used for pre-embedding electron microscopic immunocytochemistry of tissue sections from mouse sciatic nerves. In the adult, although laminin immunoreactivity was found to be predominantly associated with basement membranes as expected, the surface membranes of Schwann cells also displayed weak labelling. This distribution pattern was similar in developing sciatic nerves with the exception that laminin immunoreactivity was generally higher and also found to be present on interstitial collagen fibres. One week following sciatic nerve transection, strong laminin immunoreactivity was seen on regenerating axons growing along laminin-positive basement membrane tubes in the distal stump of the transected nerve. Our results demonstrate that laminin immunoreactivity is not restricted to basement membranes of the mouse sciatic nerve, but is also found in direct contact with adult, developing and regenerating axons as well as on the surface of Schwann cells. The finding of laminin immunoreactivity on extracellular matrix components, axons and Schwann cell membranes under conditions of growth and regeneration makes it more likely that axons are able to interact with laminin not only in vitro but also in vivo.
Aging↗
New expression of myelomonocytic antigens by microglia and perivascular cells following lethal motor neuron injury.
The results of the present study demonstrate that following lethal motor neuron injury microglia and perivascular cells, as well as brain macrophages derived from the latter two cell types, newly express antigens of the myelomonocytic lineage as recognized by the monoclonal antibodies ED1 and ED3. It is suggested that differences in the immunophenotype of resident brain macrophage precursor cells, i.e. microglia and perivascular cells, and macrophages occurring outside the central nervous system (CNS) may be explained by differences in local macrophage antigen expression rather than by a different embryological lineage. The new appearance of antigens common to peripheral macrophages on neural phagocytes in CNS lesions may therefore not necessarily imply that most or all of these cells are of recent blood origin.
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Perivascular microglia defined.
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Blood-Brain Barrier↗
Microglia: immune network in the CNS.
In recent years much progress has been made toward a better understanding of the nature and function of microglial cells. This review summarizes new developments and attempts to provide a perspective for future avenues to take in microglial research. Microglia are considered to play an active role in a variety of neurological diseases. Their function in forming a network of immune competent cells within the CNS is discussed.
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The third glial cell type, the microglia: cellular markers of activation in situ.
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Immunophenotypic characterization of rat brain macrophages in culture.
Five monoclonal antibodies specific for rat monocytes/macrophages were used to characterize macrophages/microglia bulk isolated from neonatal and adult rat brain. The majority of brain macrophages was positive for all antibodies tested with minor differences between cultures derived from developing and mature central nervous tissue. These results contrast in vivo findings indicating that most antigens of peripheral macrophages are absent from resting, activated and phagocytic microglia in situ. We conclude that brain macrophages/microglia newly express antigens of the myelomonocytic lineage when in culture and that cultured brain macrophages may be derived from different types of precursor cells normally present within the CNS.
Age Factors↗
Microglia and microglia-derived brain macrophages in culture: generation from axotomized rat facial nuclei, identification and characterization in vitro.
In order to study microglial cells and microglia-derived brain macrophages in vitro, a method has been developed which allows the transfer of mitotic microglial cells from adult rat brain into tissue culture. The studies were performed on facial motor nuclei which were explanted after axotomy of the facial nerve. Outgrowing cells were identified and characterized by (i) morphological criteria using light and electron microscopy, (ii) in vivo [3H]thymidine labeling combined with subsequent in vitro autoradiography, (iii) immunocytochemistry for vimentin, GFAP, Fc and complement receptors, MHC antigens, laminin, fibronectin, factor VIII related- and 04 antigen as well as lectin histochemistry, and (iv) functional in vitro tests. In addition, a microglial cell line was established from proliferating cells. The results indicate that perineuronal microglia rather than astrocytes, perivascular cells, oligodendrocytes or endothelial cells may become phagocytic after having been activated by axotomy in situ.
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Identity of ED2-positive perivascular cells in rat brain.
A controversial, though fundamental, issue in neurobiology concerns the nature, origin, and function of brain macrophages. By immunocytochemical analysis using monoclonal antibodies directed against rat macrophage antigens, i.e., ED1-3, Ox-41, Ox-42, and Ki-M2R, we show that a group of perivascular cells located within the basal membrane of CNS blood vessels are immunoreactive. These cells, which resemble pericytes in terms of their anatomical distribution, are distinct from resting parenchymal microglia immunologically as well as morphologically. Our results demonstrate considerable heterogeneity in the immunophenotype of resident brain macrophages, which may be part of the immune-nervous system interface.
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Increase of transferrin receptors and iron uptake in regenerating motor neurons.
After injury, motor neurons exhibit a number of metabolic and protein changes that are assumed to be part of an inherent neuronal regeneration program, which, when activated, eventually leads to functional restitution. The mechanisms underlying this regeneration are unclear, but it may be expected that factors supporting neuronal growth or survival play an important role in the restoration of neuronal integrity. A number of neuronal growth-associated proteins have been identified, but their functional roles remain unclear. This paper shows that axotomy results in a strong increase in transferrin receptors (TfRs) in regenerating motor neurons and that this phenomenon is functionally associated with an elevated uptake of exogenous iron. The association of TfR expression in regenerating motor neurons with direct uptake of iron into the brain provides evidence that iron uptake into neural tissue may be related to neuronal metabolic activation. We suggest that the enhanced capacity of regenerating motor neurons to bind transferrin and to take up iron plays an important role in neuronal repair.
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Formation of microglia-derived brain macrophages is blocked by adriamycin.
Injection of ricin, the toxic lectin from Ricinus communis, into the rat facial nerve leads to rapid degeneration of motor neurons and concomitant proliferation and transformation of endogenous microglia into brain macrophages. Using [3H]-thymidine autoradiography, immunocytochemistry for microglial markers and electron microscopy, we could show that when ricin was administered together with the cytostatic drug adriamycin, the retrogradely transported adriamycin inhibits the macrophage response induced by toxic ricin. It is concluded that under conditions of neuronal degeneration, e.g., following ricin intoxication, brain macrophages are predominantly, if not exclusively, derived from endogenous microglia.
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Neuron-glial relationship during regeneration of motorneurons.
Following axonal interruption, structural, metabolic and physiological parameters change in motorneurons. Also, glial cells are involved in this process. Microglia proliferate and express new proteins such as vimentin or MHC antigens. Astrocytes show hypertrophy, increased GFAP synthesis, and formation of lamellae. Both glial cell types participate in deafferentation and insulation of regenerating neurons, a process with significance for post-lesioning functional impairment.
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Expression of Ia antigen on perivascular and microglial cells after sublethal and lethal motor neuron injury.
The expression of immune-associated (MHC class II) antigen was studied immunohistochemically over several months in the rat facial nucleus after nerve transection and after intraneural injection of toxic ricin. Cells expressing Ia antigen were of a perivascular type and parenchymal ramified microglia. In the first few weeks after nerve lesions we observed a gradual increase in the number of Ia-immunoreactive cells starting with an initial appearance of Ia-positive perivascular cells which were succeeded by increasing numbers of Ia-positive ramified microglia. In long-term animals Ia expression was almost exclusively found in microglia. We propose (a) the existence of a population of immunocompetent perivascular cells normally present in adult rat brain that can be stimulated to express Ia antigen, and (b) the existence of a subpopulation of ramified microglia that arises through transformation of Ia-positive perivascular cells in the adult under pathological conditions.
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Peripheral nerve lesion produces increased levels of major histocompatibility complex antigens in the central nervous system.
Proliferation of central nervous system (CNS) glia in response to peripheral nerve injury occurs without apparent participation of cells of the immune system. It is shown here that following transection of the rat facial nerve there is strongly elevated expression of class I, and to a lesser extent, class II antigens of the major histocompatibility complex (MHC) in the facial nucleus. It is demonstrated by double-immunofluorescence studies that the cells responsible for increased levels of MHC class I antigens are endogenous brain microglia. These findings emphasize the thought that microglia are immunocompetent cells, but, at the same time, raise the possibility for a non-immunological function of MHC antigens under conditions of neural regeneration.
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Microglial cells but not astrocytes undergo mitosis following rat facial nerve axotomy.
Transection of the facial nerve leads to a glial response within its central nucleus of origin. Concomitant with a proliferation of satellite microglial cells an astrocytic reaction is also seen. In the present study light and electron microscopic autoradiography were performed in order to clarify whether only microglial cells undergo mitosis following facial nerve axotomy or if astrocytes also divide. Our results provide the first electron microscopical autoradiographic evidence for the labelling of endogenous microglial cells. We suggest that microglial cells are the only proliferating element during this process in the rat facial nucleus.
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5'-Nucleotidase in postnatal ontogeny of rat cerebellum: a marker for migrating nerve cells?
The distribution of the ectoenzyme 5'-nucleotidase was studied in the developing rat cerebellum using enzyme- and immunocytochemical techniques in order to evaluate its appearance in the processes of cellular migration during nervous system development. 5'-Nucleotidase enzymatic activity appeared first in the external granular layer (postnatal day 6). Then, the inner portion of the external granular layer and the developing molecular layer became prominently stained (postnatal day 12). At 21 days the adult pattern was established with a diffuse labeling of the whole molecular layer. Additionally, 5'-nucleotidase enzymatic activity was found around Purkinje cells. At the ultrastructural level migrating nerve cells exhibited an intense surface labeling whereas resting neuroblasts of the external granular layer as well as all post-migratory nerve cells were negative. Immunocytochemistry differed from enzyme histochemistry in that immunoreactivity was found to be selectively associated with glial elements. It is suggested that 5'-nucleotidase may serve as a marker for processes of neuronal migration and neuron-glia interactions during postnatal ontogeny. Underlying mechanisms could be due to an interaction of 5'-nucleotidase with the extracellular matrix molecule, laminin, and cytoskeletal actin involved in locomotion.
5'-Nucleotidase↗
Increased glial fibrillary acidic protein synthesis in astrocytes during retrograde reaction of the rat facial nucleus.
Glial fibrillary acidic protein (GFAP) increases in astrocytes following axotomy of facial motoneurons. In the present study we quantified GFAP synthesis both in regenerating facial nuclei after nerve crush and in nonregenerating facial nuclei after nerve resection. An increase in GFAP synthesis during regeneration occurs as early as 24 h after the axotomy. Thus, the increase in the astrocytic GFAP synthesis seems to be the earliest glial response to retrograde changes in facial motoneurons.
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Functional plasticity of microglia: a review.
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.
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