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Originally published online as doi:10.1189/jlb.0303114 on November 11, 2003

Published online before print November 11, 2003
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(Journal of Leukocyte Biology. 2004;75:388-397.)
© 2004 by Society for Leukocyte Biology

Microglia, macrophages, perivascular macrophages, and pericytes: a review of function and identification

Gilles J. Guillemin*,{dagger},1 and Bruce J. Brew{ddagger}

* Centre for Immunology, Neuroimmunology Department, and
{ddagger} Department of Neurology, St. Vincent’s Hospital, Sydney, NSW, Australia; and
{dagger} University of New South Wales, Sydney, Australia

1 Correspondence: Centre for Immunology, Neuroimmunology Department, St. Vincent’s Hospital, Boundary St., Darlinghurst, Sydney, NSW, 2010, Australia. E-mail: G.Guillemin{at}cfi.unsw.edu.au


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 ONTOGENY
 PHYSIOLOGIC AND PATHOLOGIC...
 MICROGLIA VERSUS MACROPHAGE
 THE PERICYTE VERSUS THE...
 CONCLUSION
 REFERENCES
 
The phenotypic differentiation of systemic macrophages that have infiltrated the central nervous system, pericytes, perivascular macrophages, and the "real" resident microglial cells is a major immunocytochemical and immunohistochemical concern for all users of cultures of brain cells and brain sections. It is not only important in assessing the purity of cell cultures; it is also of fundamental importance in the assessment of the pathogenetic significance of perivascular inflammatory phenomena within the brain. The lack of a single membranous and/or biochemical marker allowing conclusive identification of these cells is still a major problem in neurobiology. This review briefly discusses the functions of these cells and catalogs a large number of membranous and biochemical markers, which can assist in the identification of these cells.

Key Words: brain • monocyte cells • differentiation


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
ONTOGENY
 PHYSIOLOGIC AND PATHOLOGIC...
 MICROGLIA VERSUS MACROPHAGE
 THE PERICYTE VERSUS THE...
 CONCLUSION
 REFERENCES
 
The phenotypic differentiation of systemic macrophages that have infiltrated the central nervous system (CNS), pericytes, perivascular macrophages, and the "real" resident microglial cells (Fig. 1 ) is a major immunocytochemical and immunohistochemical concern for all users of cultures of brain cells and brain sections.



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  		Figure 1. Simplified schematic drawing of the myeloid cells in the brain perivascular area.

 
This review will concentrate on discussion of the available markers for identification of each cell after a review of their ontogeny and function.

For the purpose of this review, we will use the term "brain macrophage" to encompass macrophages infiltrating the brain, pericytes, perivascular macrophages, and microglia. There is a considerable heterogeneity in the phenotype of brain macrophages even within the latter groups. For example, Perry and Gordon [1 ] have emphasized three different types of microglia: radially branched (found in the gray matter), longitudinally branched (found in the white matter), and compact microglia [found exclusively in those parts of the brain lacking a blood brain barrier (BBB)]. Other investigators have differentiated granular and agranular pericytes [2 ]. Nonetheless, there does not appear to be any fundamental, functional difference between these subtypes of brain macrophage, and so, this review will only discuss the aforementioned four types of brain macrophage.


   ONTOGENY
TOP
 ABSTRACT
 INTRODUCTION
 ONTOGENY
PHYSIOLOGIC AND PATHOLOGIC...
 MICROGLIA VERSUS MACROPHAGE
 THE PERICYTE VERSUS THE...
 CONCLUSION
 REFERENCES
 
A controversial, although fundamental, issue in neurobiology concerns the nature and origin of brain macrophages. We agree with the most commonly accepted hypothesis, namely, that the most likely source for all or most brain macrophages is the monocyte. Amoeboid microglia in the developing brain, however, probably have an additional source—the pial macrophages, which in turn, are derived from mesenchymal progenitor cells in the yolk sac [3 ]. Monocytes appear to migrate into the brain from several sites during embryogenesis and may continue to enter, at least from blood vessels, in the adult state [4 ]. Once in the brain, monocytes differentiate into one of the four types of brain macrophage depending on the signals associated with the microenvironment. Although there is no definitive proof for this model, there is certainly evidence to support it. Thomas [2] cites work that has shown pericytes leaving the basal lamina and migrating to the perivascular space where they are indistinguishable from perivascular macrophages. These same cells have then been reported to migrate into the brain parenchyma, where they are indistinguishable from infiltrating macrophages [5 ]. Furthermore, the monocytes that enter the brain in the stab-wound model have been observed to "transform" into microglia. Finally, Perry and Gordon [1] have demonstrated that perivascular macrophages, pericytes, and probably microglia "turn over" from circulating monocytes. The rates of turnover vary considerably in mice: several months for perivascular macrophages and pericytes; years for microglia (although some may not turn over at all). Similar kinetics are not known for humans. It is also unknown whether particular diseases may affect these rates.

Pericytes
Pericytes are generally accepted as being of mesodermal origin [2 , 4 ]. They appear to migrate into the tissue during the latter stages of vascularization and assume their characteristic location and properties. Mesenchymal precursor cells settle on newly formed capillary sprouts and differentiate into pericytes as they become enclosed within basal lamina [6 ].

Perivascular macrophages
Based on their morphology and immunophenotype, perivascular macrophages appear to be very similar to blood-derived macrophages (see Table 2 in ref. [7 ]). Moreover, using transplants of green fluorescent protein-transfected bone marrow cells in adult mice, Bechmann et al. [5 ] concluded that brain perivascular cells are a population of migratory macrophages and not resident histiocytes. These data essentially supplant those of earlier studies such as Kida et al. [8 ] and the idea that they are distinct from pericytes, microglia, and macrophages.


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  		Table 2. Selection of ten markers allowing the differentiation between microglial cells and macrophages

 
Microglia
The origin of microglia has been one of the most controversial issues in glial research [3 , 9 , 10 ]. The large majority of neurobiologists now believe that they are derived from monocytes and to a lesser extent, from mesenchymal progenitor cells. The alternative view—that they originate from the neuroepithelium, as do neurons and other brain glial cells—is becoming increasingly unlikely.


   PHYSIOLOGIC AND PATHOLOGIC CONDITIONS
TOP
 ABSTRACT
 INTRODUCTION
 ONTOGENY
 PHYSIOLOGIC AND PATHOLOGIC...
MICROGLIA VERSUS MACROPHAGE
 THE PERICYTE VERSUS THE...
 CONCLUSION
 REFERENCES
 
In physiologic conditions, the brain contains resting microglia, perivascular macrophages, and pericytes, as well as a few "patrolling" macrophages. In pathologic situations, all these cell types are activated. Microglia and pericytes may proliferate to a limited extent in contrast to macrophages, which cannot. Commonly, in pathologic conditions affecting the brain, there is BBB disruption, which will allow entry of more macrophages from the blood.

Pericytes represent the first line of immunologic defense of the brain [11 ]; indeed, pericytes can act as antigen-presenting cells. Pericytes can inhibit endothelial cell growth, promote vessel constriction, and transform into smooth muscle cells. In essence, pericytes seem important as structural support in the microcirculation and in BBB function. Pericytes have been considered to be significant in the pathogenesis of tissue damage in hypoxia, hypertension, diabetic retinopathy, trauma, Alzheimer’s disease, multiple sclerosis, and in CNS tumor formation [7 , 12 13 14 ]. In first the 2 h after injury, pericytes and perivascular macrophages are activated and start to migrate from their original location [5 , 14 ]. Concomitantly, activated blood monocyte/macrophages and lymphocytes appear to migrate through the disrupted BBB in which the number of tight junctions has strongly decreased [15 ]. Chemoattractive molecules, particularly the chemokine monocyte chemoattractant protein-1 (MCP-1) produced by astrocytes, attract these blood monocytes [16 ]. At the same time, resting microglia become activated and change their phenotype to ameboid microglia capable of phagocytosis [17 , 18 ]. The involvement of activated microglia and perivascular macrophages associated with disruption of the BBB is a recent novel hypothesis for one aspect of the pathogenesis of Alzheimer’s disease [19 20 21 ]. It should be emphasized that the above outlined sequence of events in inflammation is very much simplified. Recent studies have also ascribed a neuroprotective role to activated microglia [22 ]. The precise signals that determine whether microglia in inflammatory states are phagocytic or neurotrophic are still to be determined.

If there are common aspects of ontogeny and function, why is it important to differentiate the types of brain macrophages? The response to this is that although there are common facets, there are distinct differences in gene expression and function. For example, there are important differences in the production of quinolinic acid (QUIN), a neurotoxin derived from tryptophan catabolism within the brain [23 ]. We and others [24 25 26 ] have shown that QUIN is elevated in several brain diseases (e.g., AIDS dementia complex, Alzheimer diseases, trauma, meningitis). QUIN may also cause gross opening of the BBB to large molecules, including proteins and immune blood cells [27 ]. Monocytic cells almost exclusively produce QUIN [28 29 30 31 ]. In brain inflammatory conditions, there is evidence suggesting a major role for resident brain macrophages in the overproduction of QUIN [32 ], which can induce production of large quantities of MCP-1 by astrocytes [33 ]. As described above, MCP-1 is one of the most potent chemoattractants for blood monocytes. We and others [29] showed that de novo QUIN production by human interferon-{gamma}-activated macrophages was 20- to 30-fold greater than microglial synthesis. Some transcriptional discrepancy might explain the lower microglial ability to produce QUIN in comparison with macrophage [31 , 34 ]. Activated microglia may be the primary endogenous cell type responsible for QUIN synthesis within the CNS in inflammatory diseases. However, under pathological conditions in which the BBB is altered and/or leukocytic infiltration in the brain parenchyma, most of the intracerebral QUIN is derived from activated macrophages. The ability of the pericyte to produce QUIN is unknown. Another important example of a difference between brain macrophages relates to the contractile properties of the pericyte [35 ]. Perivascular macrophages do not have this capacity.

With this background, it is pertinent to review methods of identifying these different types of brain macrophage.


   MICROGLIA VERSUS MACROPHAGE
TOP
 ABSTRACT
 INTRODUCTION
 ONTOGENY
 PHYSIOLOGIC AND PATHOLOGIC...
 MICROGLIA VERSUS MACROPHAGE
THE PERICYTE VERSUS THE...
 CONCLUSION
 REFERENCES
 
Most of the scientific papers concerning the characterization of the microglial cell have been published between the late 1980s and early 1990s [36 ]. Moreover, a large majority of these publications pertain to the characterization of microglial cells obtained from animals, more particularly, rodents (for review, see refs. [37 , 38 ]), and only a small proportion are concerned with human microglial cells [39 40 41 42 ]. Currently, none of these publications, even the most recent [42 43 44 45 ], describes the existence of a single, specific marker for the microglial cell, with one possible exception. Using scanning electronic microscopy (SEM), Giulian et al. [46 ] showed that microglia from postnatal rat brain are covered with spines (more than 20 per cell) in a distinctive manner, which contrasts with the smooth surfaces of bone marrow cells and the ruffled surfaces ("Rose aspect" in the tables) of tissue macrophages [47 ]. The spine-bearing surface of microglia appears to be a specific cell marker, which is not changed with age or a variety of immunostimulants. However, SEM is a complicated method, which cannot be technically used in many in vitro, ex vivo, and in vivo studies. It is still necessary to use several markers together to be able to accurately and easily differentiate macrophages from microglia.

Characterization of the microglial cells is even more difficult, as these cells share several antigens with different cell types (Table 1 ), including macrophages (CD11b, CD68), endothelial cells [vascular cell adhesion molecule 1 (VCAM-1)], lymphocytes [lymphocyte function-associated antigen (LFA), leukocyte common antigen (LCA), laminin 1 (LN-1)], and oligodendrocyte (GD3). Moreover, published studies about the expression of some microglial markers are occasionally contradictory (Table 1) . It is important to highlight that in all these studies, the expression of biological and biochemical microglial markers may vary according to parameters, such as the following examples.


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  		Table 1. Review of membranous, biochemical and morphological markers of activated microglial cells in comparison with blood derived macrophages

 
The cell activation
As for monocytes and macrophages, there are marked variations in the expression of membranous markers and in the biochemical activities between the nonactivated microglial cell (ramified) and the activated microglial cell [67 ]. Changes in the cell morphology are, of course, very significant [38 , 46 , 143 , 144 ].

The cell maturation
Differences in maturation between microglial cells derived from adult or fetal tissue are another major parameter influencing the expression of markers [145 ]. To our knowledge, there is no one study that has compared the phenotypic expression between adult and fetal microglial cells from the same species.

The interspecies variations
Even if the microglial markers are the same between species, some differences in function can, however, be found [130 ]. For example, murine microglial cells are not able to produce the neurotoxin quinolinic acid, whereas human cells can [31 ], and murine cells exhibit differences in the migratory response to chemokines [145 ].

The cell-culture conditions
To maintain healthy microglial cells in vitro, the culture medium has to be complemented with growth factors such as macrophage-colony stimulating factor (M-CSF) and granulocyte M-CSF (GM-CSF) [49 , 146 , 147 ], with cytokines such as interleukin-3 [49 ], or with commercial supplements such as B-27 [147 , 148 ] or N2 [149 ]. The presence of such growth factors in the culture medium may also influence the expression of the microglial markers.

The phenotypic heterogeneity
Lastly, as for the astrocyte, different microglial subpopulations are present in the CNS and display a marked functional and phenotypic heterogeneity [85 , 150 151 152 153 154 155 ].

Table 1 reviews, in a nonexhaustive manner, a large number of membranous, biochemical, and morphological markers of activated microglial cells (whatever the species) in comparison with blood-derived macrophage. Two major sources of information can be used to obtain complementary data on each single CD: Leucocyte Typing VI [70] and the NIH Website http://www.ncbi.nlm.nih.gov/prow/guide/45277084.htm.

Of note, a monoclonal antibody (5-D-4) directed against a surface epitope (hypersulfured keratane sulfate) is able to specifically recognize ramified microglial cells but not ameboid microglial cells, monocytes, or macrophages [156 ].

Characterization of the microglial cell versus the peripheral macrophage has been examined in only a limited number of studies [7 , 38 , 46 , 48 , 67 , 135 , 156 157 158 ]. As described above, the combined detection of three or four markers can lead to a quasi-certain identification of the microglial cell. Several studies using flow cytometry or classic immunocytochemistry or immunohistochemistry defined a profile of characterization of the microglial cell corresponding to the following phenotype: CD68+, CD45 low, CD11b+, CD11c high, MHC class II+ and CD14– [41 , 45 , 47 , 48 , 64 , 159 , 160 ]. Among all the myeloid cells, it seems that only the microglia cell appears spurred with spikes on SEM [46 , 47 ]. This morphologic appearance is valid for more than 99% of the microglial cells, does not change with age, and is not modified by the cellular activation from cytokines. Finally, some other markers, such as the capacity to proliferate in vitro [38 , 41 , 47 ], the production of LN [47 ], the peroxidase activity [38 , 48 ], as well as the RFD7 expression [48 ], can add important complementary information. Table 2 summarizes the selection of these markers.


   THE PERICYTE VERSUS THE MICROGLIA AND THE PERIVASCULAR MACROPHAGE
TOP
 ABSTRACT
 INTRODUCTION
 ONTOGENY
 PHYSIOLOGIC AND PATHOLOGIC...
 MICROGLIA VERSUS MACROPHAGE
 THE PERICYTE VERSUS THE...
CONCLUSION
 REFERENCES
 
The pericyte is another myeloid cell type often located adjacent but distinct from the perivascular macrophage [161 ]. However, it is far easier to distinguish a microglial cell from a pericyte than from a macrophage. There are several parameters allowing relatively easy differentiation between pericyte and microglia:

The localization
The pericytes are associated with the brain microvasculature, where they are entirely contained within the basal lamina on the abluminal surface of endothelial cells. Pericyte cell processes are located over the endothelial cells tight-junction regions [162 ]. Microglia do not have direct contact with endothelial cells, as the latter is sheared by astroglial terminations (Fig. 1) .

The morphology
CNS pericytes are polymorphs. They can have an oval-to-elongated cell body with branching processes, which encircle the blood vessel (Fig. 1) [2 ]. As for microglia, CNS pericytes can display a marked heterogeneity in vitro. When grown on plastic, pericytes can appear as large, irregularly shaped cells. Their morphology is more likely that of an astrocyte than a microglial cell [163 , 164 ].

The capacity of proliferation
In culture, microglia and pericytes have a very slow doubling time, and they never reach confluence [165 ]. In addition, the pericyte has very poor, plated efficiency (<50%), whereas microglia have the capacity to strongly attach to plastic. Phosphatidylcholine (PC) and microglia appear to be relatively resistant to trypsin [47 , 165 ].

The immunochemical markers
As for microglia, no single, specific marker has been identified for the pericyte yet. However, there are some markers that are much more likely to be associated with PC, such as RGS5, which is a member of the RGS family of GTPase-activating proteins [166 ], the cell-surface 3G5 ganglioside antigen [167 , 168 ], the platelet-derived growth factor (PDGF)-ß receptor [169 ], and the high molecular weight melanoma-associated antigen (HMW-MAA). The latter is specific for microvascular pericytes but is only detected in proliferating cells [170 ]. RGS7 is express by microglia [171 ] but not RGS5 [172 ]; 3G5 is present on neurons but not on microglia [173 ]; and the PDGF-ß receptor can be expressed by microglia [174 ].

As for microglia, a simple association of one of the above markers together with one of the many macrophage markers expressed by the pericyte [2 ] such as MHC classes I and II molecules [175] would be enough to specifically identify brain (PC) from other brain cells (Table 3) .


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  		Table 3. Review of membranous, biochemical and morphological markers of activated microglial cells in comparison with pericytes

 

   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 ONTOGENY
 PHYSIOLOGIC AND PATHOLOGIC...
 MICROGLIA VERSUS MACROPHAGE
 THE PERICYTE VERSUS THE...
 CONCLUSION
REFERENCES
 
Although many questions remain unanswered in regard to the various types of brain macrophages, newly developed methodologies hold promise. Among these are probably laser capture microdissection and gene array. The former could be used to obtain the relevant type of brain macrophage, and the latter could be used to determine which genes are up- or down-regulated in each cell. With this knowledge, more specific and perhaps diagnostic markers could be developed.


   ACKNOWLEDGEMENTS
 
The St. Vincent’s Clinic Foundation, the NHMRC, the NSW Health Department, and the UNSW have supported this work.

Received March 19, 2003; revised August 17, 2003; accepted September 23, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 ONTOGENY
 PHYSIOLOGIC AND PATHOLOGIC...
 MICROGLIA VERSUS MACROPHAGE
 THE PERICYTE VERSUS THE...
 CONCLUSION
 REFERENCES
 

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