Accuri C6 Flow Cytometer System
Originally published online as doi:10.1189/jlb.0608385 on November 21, 2008

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(Journal of Leukocyte Biology. 2009;85:352-370.)
© 2009 by Society for Leukocyte Biology

Microglia: gatekeepers of central nervous system immunology

Bart R. Tambuyzer*,{dagger},1, Peter Ponsaerts{dagger} and Etienne J. Nouwen*

* Laboratory of Neurobiology and Neuropharmacology, Department of Biomedical Sciences, and
{dagger} Laboratory of Experimental Haematology, Vaccine and Infectious Disease Institute (Vaxinfectio), Faculty of Medicine, University of Antwerp, Belgium

1 Correspondence: Laboratory of Experimental Haematology, Vaccine and Infectious Disease Institute (VIDI), University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium. E-mail: bart.tambuyzer{at}ua.ac.be


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ABSTRACT
 
Microglia are perhaps the most underestimated cell type of our immune system. Not only were immunologists unaware of their capabilities until recently, but also, some neuroscientists denied their actual existence until the late 20th century. Nowadays, their presence is confirmed extensively, as demonstrated by numerous reports describing their involvement in virtually all neuropathologies. However, despite distinct approaches, their origin remains a point of controversy. Although many agree about their myeloid-monocytic ancestry, the precise progenitor cells and the differentiation mechanisms, which give rise to microglia in the different developmental stages of the CNS, are not unraveled yet. Mostly, this can be attributed to their versatile phenotype. Indeed, microglia show a high morphological plasticity, which is related to their functional state. This review about microglia aims to introduce the reader extensively into their ontogeny, cell biology, and involvement in different neuropathologies.

Key Words: review • immune function • activation • neuropathology


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MICROGLIA: AN HISTORICAL PERSPECTIVE
 
The earliest report of microglia can be traced back to the late 19th century. The psychiatrist Nissl [1 ] encountered rod cells in the CNS and described them as reactive glial elements with the ability to migrate, proliferate, and perform phagocytosis. Next, Santiago Ramón y Cajal in 1913 [2 ] was the first to determine a third element in the CNS next to—in that time—commonly known neurons and astrocytes, a distinction he made based on morphological differences. However, Pio del Rio-Hortega [3 ], a Spanish neuroanatomist, was the first to divide this third element into oligodendroglia and microglia. Using silver-staining methods and light microscopy, he described several fundamental characteristics of microglia that are still considered to be of relevance for current research about microglia. In his work, he concluded that microglia originated from the invasion of mesodermal pial elements into the nervous system, but he also speculated about blood mononuclear cells as a potential source. His novel insights, together with the limitations of the silver-staining methods as the only identification procedure for many decades, gave rise to a long-lasting controversy about microglial ontogeny.


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ORIGIN OF MICROGLIA
 
The developmental origin of microglia has been a subject of debate for many years since del Rio-Hortega [3 ] first described this cell type in 1932. Nowadays, most researchers support the hypothesis that microglia are derived from myeloid-monocytic cells and/or their hematopoietic precursors (for reviews, see refs. [4 , 5 ]). Following this hypothesis, microglia or their precursors should enter the CNS at a certain point and migrate and differentiate to ultimately colonize the whole CNS parenchyma. In contrast, others believe that microglia are derived from neuroectodermal matrix cells [6 ], which are able to differentiate into microglia locally. The latter implies a common ancestry for microglia and macroglia, such as astrocytes and oligodendrocytes. In addition, some other schools support the hypothesis that microglia originate from pericytes [7 ] or from the subependyma adjacent to the lateral ventricles [8 ].

Here, we will review in depth the two most important hypotheses for microglial origin: "neuroectodermal" or "myeloid-monocytic." For the latter, we will also discuss migration and differentiation of microglia (or their precursors) in the developing CNS. Although this myeloid-monocytic origin for microglia has been widely accepted now, the neuroectodermal hypothesis remains interesting from a historical perspective.

Microglial precursors
Neuroectodermal precursors
The view that microglia are derived from neuroectodermal progenitor cells has been proposed by several independent researchers using different techniques. Skoff [9 ], who used a rat model of optic nerve degeneration and optic nerve development in combination with 3H-autoradiography and electron microscopy, was the first to detect a so called "multipotential glia cell". According to the data, these cells originated from neuroectodermal matrix cells and not from invading mesenchymal cells. This was confirmed using the same techniques in newborn mice, where a continuous morphological transition was observed between glioblasts and "resting" (=ramified) microglia in the developing gray matter of the hippocampus [10 ].

Second, others were able to identify microglia precursors in the germinal matrix of the CNS based on lectin [Ricinus communis agglutinin 1 (RCA-I)] or immunohistochemical stainings [11 , 12 ]. The glial raphe of the floor plate of the hindbrain and spinal cord were pinpointed as the site of microglia origin through immunohistochemical staining for lipocortin-1 (annexin-I). Disialoganglioside GD3 is another molecule described to be specific for microglia and is also expressed on neuroectoderm, oligodendrocytes, and specific neuron populations [13 ]. However, sharing markers does not always imply a common ancestry.

A third series of experiments supporting the neuroectodermal origin hypothesis involved cell culture experiments using brain tissue from different developmental stages, appropriately discarded of blood (vessels) and meninges, from which microglia could be recovered. In this experimental set-up, microglia were derived from their progenitors in neopallial cultures of embryonic and newborn mice after nutritional deprivation [14 ]. In addition, this study was expanded by culturing the neopallial cells in Grenier hybridoma tissue-culture dishes. This led to heterogeneous clones of astroglia and microglia, supporting the common progenitor hypothesis [15 ]. The fact that microglia and astroglia could have a common origin was also corroborated by a report about hematopoietic stem cells as a source for both cell types in adult mice brain [16 ]. However, in this study, hematopoietic stem cells were derived from bone marrow and could have been contaminated with other progenitor cells, which might explain their divergent differentiation potential.

Hematopoietic stem cells
The appearance of microglia in the developing brain before onset of vascularization [17 ] or before the appearance of monocytes in hematopoietic tissues [18 ] favors hematopoietic stem or progenitor cells to be the source of microglia in situ. Initial attempts to demonstrate the presence of hematopoietic stem cells in the mammalian brain were undertaken by injecting cells of dissociated brain tissue into irradiated mice [19 ]. A significant number of CFUs were found in the spleen, leading to the conclusion that hematopoietic stem cells might colonize the CNS during embryogenesis. However, others used the same experimental model but washed the brains extensively prior to cell dissociation [20 ]. In addition, methylcellulose cultures were performed to detect GM-CFUs [21 ]. Only few colonies were observed, leading to the conclusion that the hematopoietic stem cells recovered by Bartlett [19 ] were of contaminating blood origin. In contrast, Alliot et al. [22 ] reported the existence of hematopoietic stem cells that can, next to differentiation into blood cell types, transform into microglia in the developing and adult CNS of mice. Experimental evidence demonstrated that these cells could be traced back to the yolk sac and produced microglia already in early embryogenesis [23 ]. To this extent, a subpopulation of bone marrow cells was identified, sharing the same highly specific ion channel pattern as microglia [24 ], suggesting a precursor role for these cells.

Another approach involved the use of chimeric animals. Following irradiation, host animals were injected with bone marrow cells expressing a different MHC class I haplotype. However, only few microglia (-like) cells were identified within the CNS even after a long recovery time [25 ]. The same setup, combined with a model of experimental allergic encephalomyelitis (EAE) to up-regulate expression of MHC class I in CNS immunocytes, gave rise to similar results [26 ]. To overcome problems as a result of marker expression, bone marrow cells from bacteriophage-infected transgenic mice were used as a donor. Despite the presence of this stable marker, only few donor-type microglia could be detected in host CNS [27 ]. Recently however, transplantation of GFP+ mice bone marrow cells in GFP– host mice revealed the presence of many GFP+ microglia throughout developing and/or inflamed CNS [28 , 29 ]. In conclusion, although some claim that microglia themselves can serve as pluri/multipotential stem cells to form neurons, astrocytes, and oligodendrocytes in vitro [30 , 31 ], markers distinguishing microglia univocally from other cell lineages in the CNS or the peripheral system have yet to be defined.

Monocytes/macrophages as direct progenitors
According to the model of Van Furth [32 ], microglial origin should be classified into the mononuclear phagocyte system. Indeed, amoeboid and ramified microglia express the two most important markers characteristic for this system: the FcR and the complement receptor III (CR3) [33 , 34 ]. In addition, amoeboid microglia are capable of performing phagocytosis in vitro [35 ] and in vivo [36 ]. Although these characteristics constitute the minimal requirements to be a "true" mononuclear phagocyte, it does not exclude a nonmonocytic origin for microglia. Several other markers shared by microglia with monocytes and/or macrophages have been used to sustain the monocyte origin hypothesis: e.g., enzyme cytochemical stainings for nucleoside diphosphatase, acid phosphatase, nonspecific esterase (NSE) [37 , 38 ] vaults (large-size ribonuclear protein particles) [39 ], and in particular, lectin staining (e.g., Griffonia simplicifolia isolectin-b4, RCA, wheat germ agglutinin, and Con A) [40 ]. However, these observations do not permit us to outline a straightforward staining for all microglia to confirm their monocytic origin. Frequently, amoeboid microglia stain intensively, but their ramified counterparts do not express the same markers [40 , 41 ]. Also, as described above, microglia share some markers with astroglia and oligodendrocytes [13 , 42 ]. In addition, microglia display specific characteristics such as proliferation in vitro [35 ] and in vivo (see Proliferation) and a specific ion channel pattern [43 ], which are different as compared with monocytes/macrophages.

Several interesting studies performed by Ling and colleagues [44 ], in which colloidal carbon particles were injected to follow blood monocytes into the developing rat CNS, demonstrated that monocytes that had ingested the carbon particles peripherically appeared as amoeboid microglia in the developing CNS and later on as ramified cells. The same investigators repeated these experiments with rhodamine B isothiocyanate [45 ]. Although most of the microglia initially appear during perinatal CNS development through recruitment of their progenitor cells, their population is sedentary in the normal adult CNS and is replenished only partially by monocytic/myeloid precursors under pathological circumstances [26 ]. However, in some models, e.g., EAE [46 ] and ischemic retinopathy [29 ], an accelerated turnover of microglia by bone marrow-derived cells circulating in the blood was observed. In addition, indirect support for a monocytic origin was supplied by a study showing depletion of amoeboid microglia in postnatal brain after administration of glucocorticoids, which are known to be strong immunosuppressors [47 ].

New concepts
An interesting recent study performing chimeric bone marrow transplantations points out that microglia as a population balance between mitosis and apoptosis during inflammation to control their numbers [48 ]. Moreover, following irradiation of the host, they demonstrate that resident microglia are complemented with a small population of migrating microglia originating from bone marrow transplants. In addition, they demonstrated that the number of resident microglia in their chimera model—microglia expected not to be killed by irradiation—was reduced up to 30% in lesion-induced inflammation and that they were severely affected in their mitotic ability. To further demonstrate the bone marrow-derived origin of microglia, experiments were performed in which two circulating systems of different mice were interconnected (i.e., parabiosis). In this set-up, supply of labeled cells to the recipient mouse did not result in a contribution to the microglial population in these hosts, even after inflammation was evoked [49 ]. However, only when irradiation was combined with bone marrow injection, donor-derived microglia were observed in brain tissue. The latter suggests for an experimentally induced migration of bone marrow-derived precursors after irradiation and injection in the bloodstream as used in many other (older) studies (see Hematopoietic stem cells and Monocytes/macrophages as direct progenitors), perhaps not truthfully mimicking true microglial ontogeny processes. In contrast, Mildner and colleagues [50 ] designate Ly-6ChiCCR2+ monocytes as microglial precursors but also underscore the need for irradiation of the brain to induce migration of microglial precursors. From these new studies, using bone marrow/monocytes in combination with irradiation to demonstrate migration/origin of microglia, it can be concluded that caution should be taken to design a relevant study model, as each experimental set-up currently used might harbor several important complications as commented by Ransohoff [51 ].

Entry of microglial precursors in the CNS
A massive appearance of microglia is seen around birth in different species; i.e., the so-called "developmental window" of these cells [6 ] at a time vascularization of the CNS is already completed. However, microglia also appear, to a lesser extent in embryonic life [18 , 23 ], in the avascular CNS. Moreover, the neuroectodermal origin hypothesis would implicate their presence within the developing CNS, as suggested by McKanna [12 ].

If microglia originate from a source—in casu monocytes or myeloid precursors—outside the CNS, they would have a site of entry at some point. The completed vascularization of the CNS forms the perfect basis for a widespread microglial colonization. Indeed, several researchers support monocyte recruitment from the bloodstream as a basis for the expansion of microglial cell populations [33 , 39 , 44 ]. As one can expect, the brain endothelium plays a key role in this process by expressing adhesion molecules ICAM-1 [52 ] and -2 [53 ] as homing receptors.

A second possibility of microglial entrance into the CNS is via the ventricles by passing the ventricular surface. Ventricular macrophages were also observed in the developing brain and were associated closely with the appearance of microglia in the corresponding nervous parenchyma [4 , 54 ]. In addition, one study was able to track microglial cells while passing the ventricular surface [55 ].

Third, it has been suggested that microglia are derived of a meningeal source. As del Rio-Hortega [3 ] described the invasion of pial elements, several others demonstrated precursors crossing the pial surface to become microglia [56 ]. In addition, a report in avian embryos suggested that microglia invade the CNS and through proliferation, populate the entire CNS [57 ].

Proliferation, migration, and differentiation
Upon arrival in the CNS, microglial precursors are expected to undergo three major processes toward becoming a fully differentiated microglial cell: proliferation from a "precursor group", migration of the expanded cells to populate different CNS regions, and differentiation of the amoeboid microglia into their ramified resting phenotype. Throughout these processes, microglia undergo many transformations, a sequence of events often referred to as "developmental plasticity".

Proliferation
Several molecules, among them IL-3, IL-6, GM-CSF, and CSF-1, have been demonstrated to be potent stimuli for microglia in vitro [58 59 60 61 ]. For all of these cytokines, microglia express the appropriate receptors [61 ]. In addition, all of the growth factors mentioned above can be produced locally in the CNS [62 63 64 65 ]. Several in vivo studies using "proliferating cell nuclear antigen" [66 ], Ki67 [67 ], BrdU [68 ], and autoradiography [69 ] have confirmed the hypothesis that microglia can proliferate in a developing brain environment.

Migration
Nowadays, it is common knowledge that microglia are capable of migrating toward damaged neural tissue to clear the site of injury when necessary [36 , 70 ]. However, the mechanisms thriving microglia to populate the CNS after arrival at entrance gates are poorly understood. According to extensive studies about quails by Navascués and co-workers [71 ], microglial migration during development occurs in a two-step process: tangential migration followed by a radial movement pattern. Microglia have been shown to migrate tangentially along nerve fibers (so-called "highways") in the retina [72 ], through the stratum album centrale in the optic tectum [55 ] and along the developing white matter in the cerebellum [73 ]. At least in the retina, this process takes place on a substratum of Müller cell endfeet [72 ]. Radial migration from these highways has been described clearly using confocal microscopy in quail retina [74 ]. The latter has also been described for humans by Rezaie and Male [66 ], who reported that microglial invasion advances in radial waves along radiating cortical vessels and radial glial fibers. They pinpointed the importance of adhesion molecules, such as ICAM-2 and PECAM, on cerebral blood vessels and the production of the chemokines MCP-1 and RANTES. In addition, these migratory processes can be triggered by extensive cell death necessary for CNS remodeling during development [75 ], although these events are not always related [76 ].

Differentiation
It is largely accepted now that microglia acquire a ramified morphology at their final location in the CNS parenchyma [77 ]. This ramification process has been reported to occur simultaneously during radial migration of microglia [74 ]. The migratory properties of ramified microglia have also been confirmed in vitro [78 ]. Observations of intermediate forms between amoeboid and ramified microglial subpopulations further support the ramification hypothesis [33 , 45 , 66 ]. Also, during morphological transformation, the microglial phenotype changes drastically: CD11b, MHC I and MHC II, lectin, and CD45 immunoreactivity decreases or disappears [17 ], and enzymatic activity, e.g., NSE, abolishes with the transformation of an amoeboid microglial cell to the ramified form [41 ]. The ramified resting state of microglia in the CNS is induced and sustained via direct contact between neuronal cells and microglia involving a CD200 (neurons)–CD200R (microglia) interaction. CD200, expressed constitutively by neurons and CNS endothelium, provides an inhibitory signal for microglia [79 ].

In addition, several in vitro studies validated the in vivo observations. Isolated amoeboid microglia can acquire the resting ramified phenotype when cocultured on top of astrocytes [80 ] or epithelial cell layers [80 , 81 ]. Even more, microglia can perform transmigration through a renal epithelial monolayer in vitro, acquiring the ramified morphology under these cells [82 ]. Ramification in vitro is reversible [83 ], mimicking the process of dedifferentiation in vivo. Soluble factors able to induce ramification include vitamin E [84 ], DMSO, and retinoic acid [35 ], GM-CSF and/or M-CSF/GM-CSF combinations [85 86 87 ], and conditioned media [81 ]. In general, it is assumed that serum inhibits ramification [85 , 88 ], although some maintain the view that microglia do not ramify in absence of serum [81 ]. The molecular mechanisms allowing ramification remain to be elucidated, although the formation of stable-acetylated and detyrosinated microtubules seems to be necessary for the transition of amoeboid microglia into ramified cells [89 ].


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DISTRIBUTION, MORPHOLOGY, AND MICROGLIAL MARKERS
 
Distribution
Microglia are estimated to comprise 5–20% of all glial cells in the CNS [90 91 92 ]. Assuming there are 10 times more glia than neurons in the CNS, there are as much microglia as there are neurons [93 ]. However, there seem to be regional differences in the distribution of microglia in the CNS, as they appear more in the gray than in the white matter [3 , 33 , 91 ]. In addition, microglia are sparser in regions such as the hippocampus and the dorsal thalamus in the developing CNS [33 ]. In the adult mouse, the highest microglial densities are found in the hippocampal formation, the olfactory telencephalon, portions of the basal ganglia, and the substantia nigra (SN) [90 ]. Moreover, microglia are distributed unevenly within the mouse hippocampal regions and the cerebellum [94 , 95 ].

Morphology
The term developmental plasticity describes the processes of morphological/phenotypical transformation of amoeboid microglia into the ramified form during development (vide supra). However, these resting ramified microglia are capable of dedifferentiating in the amoeboid form: a process often referred to as "functional plasticity" [92 ]. Based on studies of the normal adult brain and on pathophysiological studies, three major differentiation states of parenchymal microglia can be distinguished [90 ]. Under normal circumstances, they appear as ramified, resting microglia; upon environmental stimulation, they become activated, nonphagocytic microglia with a "bushy" appearance (for an example, see Fig. 1 in ref. [96 ]); when stimuli persist, they acquire the amoeboid phenotype, a fully functional, phagocytic microglial cell. However, the definition of ramified microglia as "resting" has been challenged recently as a result of the observations that ramified microglia can migrate in vitro on an astrocyte monolayer at 20–35 µm/h [79 ]; ramified microglia posses a highly dynamic plasticity with constantly protruding and retracting branches, as demonstrated by in vivo two-photon laser-scanning microscopy [97 , 98 ]. In view of the latter, microglia scan the CNS parenchyma completely every few hours [99 ].

Topographical differences in morphology have also been reported for ramified microglia [33 , 93 ]. In gray matter, their processes usually are organized in a radiate manner. In contrast, in white matter, their cytoplasmatic extensions align parallel or perpendicular to nerve fiber tracts. In this way, the shape of the ramified microglia is well adapted to the architecture of the CNS region they populate. Not only does the structure of the CNS influence the microglial morphology, but also, the type of neuronal degeneration affects the transition of ramified microglia (for a review, see ref. [96 ]). Indeed, morphological transition of ramified microglia toward a bushy appearance is associated with anterograde axonal, and terminal synaptic degeneration, toward a "rod cell"-like morphology, is associated with dense dendritic degeneration; clusters of hyper-ramified microglia are observed around degenerating, single neurons. In this sense, the term bushy, as described above, may cover a heterogeneous group of activated microglia morphologically designed to a specific context.

Microglial markers
For a long time, microglial characterization was limited to silver carbonate staining [3 ]. The difficulty in describing a uniform characterization procedure for microglia lies in their interchangeable phenotype and concomitant differences in expression profile. The following table summarizes a large number of common membrane and intracellular proteins expressed by primary microglia in vivo and in vitro; proteins expressed constitutively during all differentiation stages are printed in bold, and the other proteins are associated with microglial activation (Table 1 ). The functional relevance of these proteins will be discussed further in the context of microglial activation and neuropathology.


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  		Table 1. Microglial Markers


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MICROGLIA VERSUS MACROPHAGES: DIFFERENCES AND SIMILARITIES
 
Microglia are comprised into the myeloid-monocytic compartment on the basis of markers and the immune-effector functions they can display (see above). However, this leaves a lot of space for interpretation, especially when trying to distinguish parenchymal microglia from infiltrating macrophages associated with a particular neuropathological lesion. Moreover, perivascular macrophages within the CNS are being replenished continuously by peripheral blood monocytes or bone marrow-derived cells [146 ]. The story is complicated further by the fact that infiltrating monocytes/macrophages can acquire a phenotype in the CNS that is, at least morphologically, indistinguishable from the microglial appearance [147 ]. Even more, activated amoeboid microglia, depending on the stimulus, can exert virtually all macrophage-associated immune functions. Nevertheless, a clear-cut distinction between these populations is indispensable to identify initiators and/or contributors within CNS lesions of different etiology.

The first attempt for such a division was made by flow cytometry. In this study, microglia were differed from monocytes and macrophages based on differences in CD11b/CD45 expression: Microglia are characterized as CD11b+/CD45low, and monocytes/macrophages are characterized as CD11b+/CD45high [148 ]. In another study, which ex vivo-phenotyped human microglia, these cells were also designated as CD11b+/CD45low [149 ]. In addition, Ulvestad and colleagues [105 ] described that microglia do not express typical macrophage markers, such as NSE, calprotectin, lysozyme, and CD14; however, others demonstrated a low-to-moderate level of expression for these proteins [87 , 147 ]. A "multiple label" definition was supplied by Dick and co-workers [150 ], identifying resident microglia as CD45low:CD4–:CD11b+:CD11chigh:MHCII+:CD26–:CD14– and activated microglia as CD45low/medium:CD4low:CD11b+: CD11chigh:MHCII+/++:CD26–:CD14–. A recent report reviews extensively the distinction between activated microglia and macrophages. In their conclusion, the authors describe that the proliferation capacity of microglia, the expression of laminin, CD11chigh, and CD45low, and the absence of CD14 and peroxidase activity are specific for the microglial phenotype, whereas macrophages display the opposite for these characteristics [147 ]. In addition, the authors suggest that microglia are best distinguished from macrophages by their spiky appearance, as demonstrated by scanning electron microscopy, and macrophages have a ruffled surface (Rose-like aspect). Unfortunately, this method has its technical limitations and cannot be unified in many experiments and/or laboratories.


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MICROGLIAL FUNCTION
 
Phagocytosis and antigen presentation
Attracted by endogenous and exogenous chemotactic factors, microglial cells have the capacity to migrate toward a site of injury or infection in the CNS [151 , 152 ]. For this, they display up-regulated expression of receptors to sense signals associated with tissue damage or inflammation and secrete proteases, autocrine, and/or paracrine mediators, allowing them to move through CNS tissue [90 ]. An orchestrated process of microglia migration combined with proliferation allows microglia to reach sufficient cell numbers at the site of inflammation or tissue damage [153 ].

As "first line of defense guardians", a typical feature of the fully activated/capacitated microglial cell is to perform phagocytosis. As a result of the highly specialized CNS environment, this process has to be controlled tightly, thereby provoking the least possible collateral damage. During CNS development, regressive phenomena accompanied by naturally occurring cell death are common. Microglia are known to function as transitory phagocytes responsible for clearing apoptotic neuronal cell bodies during CNS ontogeny [75 ]. In EAE, it has been shown clearly that microglia are responsible for phagocytosis of infiltrated T cells that underwent apoptosis [154 ]. At least in vitro, this phagocytic process involves a scavenger receptor CD36 and lectin-, integrin-, and/or phosphatidyl-mediated recognition [155 , 156 ]. Several cytokines—among them, GM-CSF, M-CSF, TNF-{alpha}, TGF-β, IL-4, IFN-β, and IFN-{gamma} [156 157 158 159 ]—are able to influence the phagocytotic properties of microglia, but also, exogenous stimuli, such as morphine, PMA, and LPS, can modulate uptake and processing of antigens and cellular debris [156 , 160 ]. The importance of phagocytosis in several neuropathologies will be discussed in detail below (see Microglia and CNS diseases).

In the normal CNS, APC are confined mainly to dendritic cells (DC) and macrophages of the meninges, choroid plexuses, and perivascular spaces [129 ]. MHC class I and class II molecules are constituvely expressed by microglia, although at low levels [114 , 115 , 161 ], as they are actively down-regulated by the immune-quiescent microenvironment of the CNS [162 ]. However, upon infectious neuropathology or autoimmune disease, but to a much lesser degree in trauma, ischemic, or neurodegenerative conditions, these molecules are up-regulated readily, which convert microglia into APC comparable with DC, the so-called experts in antigen processing and presentation inside as well as outside the CNS. Currently, there is accumulating evidence that under these conditions, microglia up-regulate MHC expression together with the costimulatory molecules CD11a, CD54, CD58, CD80, and CD86, all essential for optimal APC function and T cell stimulation [163 , 164 ]. However, to avoid excessive inflammation in the CNS, as this reaction cannot take the same proportions as in peripheral tissues without causing massive bystander damage, the activation of counter-regulatory mechanisms is indispensable. Indeed, for this purpose, microglia are capable of expressing Fas ligand (FasL; CD95L) in vitro [165 ] and in EAE lesions [166 ], implicating their role in the Fas (CD95)-FasL-mediated T cell apoptosis. Moreover, microglia themselves can express Fas [166 ], indicating that microgliosis in neuropathology can be self-limiting by eliminating not only infiltrating, inflammatory cells but also the excess of microglia by apoptosis.

Radical production
Depending on the species, microglia can produce different types of free radicals. Porcine and human microglia mainly produce superoxide radicals upon stimulation, and murine microglia mainly produce NO [167 ]. Several stimulants promote NO production in rodent microglia, e.g., cytokines, Aβ, thrombin, zymosan, chromogranin, prions, HIV-associated Tat, and ATP [142 , 168 ]. On the other hand, Aβ, IFN-{gamma}, and PMA are able to induce superoxide formation [168 ]. NO and superoxide production by microglia can also be modulated by pro- and anti-inflammatory cytokines and/or growth factors [87 , 169 , 170 ]. In addition, phagocytosis itself serves as an inducer of free radical production, for which these reactive oxygen species (ROS) are supporting the degradation of the ingested antigens and cellular debris.

Production of immunoregulatory molecules
Chemokines
Especially during their activated state, microglia can express and secrete a broad spectrum of chemokines [171 ] (Table 2 ). These are small peptides (8–14 kDa) playing a crucial role in cellular migration and intercellular communication in normal tissues, including brain, but even more during inflammation. On the basis of their structural characteristics, according to the sequence motif of conserved N-terminal cysteine residues, they can be divided into four families: CXC, CC, XC, and CXC3 [187 ]. Chemokines act through signaling their cognate chemokine receptors [187 ] and can be up-regulated in microglia in vivo during normal CNS development (CXCL1 [172 ]) but also under neuropathological conditions such as multiple sclerosis (MS; CCL3/MIP-1{alpha} [188 ]), ischemia (CXCL8/IL-8 [173 ]), Alzheimer disease (AD; CCL2/MCP-1 [189 ]), and different bacterial (CCL5/RANTES [190 ]) or viral infections (CCL4/MIP-1β [181 ]). In addition, microglial proliferation/survival, migration, cytoskeleton reorganization, and cytokine production can be affected by chemokines acting through several receptors found on microglia (Table 2) . Also, during microglia colonization of the CNS, a major role has been attributed to the expression of, e.g., CCL2/MCP-1 and CCL5/RANTES in nervous parenchyma [66 ].


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  		Table 2. Microglia and Chemokines

Cytokines
Another group of important signaling molecules for microglia includes a large number of cytokines (Table 3 ). These small proteins are usually expressed/secreted by microglia under inflammatory conditions. Important exogenous factors capable of cytokine induction in microglia are viral envelope proteins, bacterial cell wall components [LPS, leukotriene A (LTA)], bacterial DNA, and prions [214 ]. Endogenous inducers are inflammatory mediators, such as platelet-activating factor (PAF), lipids, serum proteins, or complement factors, but also, disturbed ATP and [K+] levels can cause microglial activation [133 ].


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  		Table 3. Microglia and Cytokines

IL-1 and TNF-{alpha} are two proinflammatory cytokines with diverse influences and many common functions, which can be produced by microglia [215 ] and can also serve as autocrine activators [216 , 217 ]. These cytokines are mainly involved during initiation of neuroinflammation by their ability to induce expression of the adhesion molecules and chemokines necessary for attraction of leukocytes [218 , 219 ]. In addition, these processes can be aggravated by IFN-{gamma}, mainly produced by CD4+, CD8+ T cells, and NK cells but also by macrophages/microglia upon an IL-12- and IL-18-mediated stimulation, thriving the immune response toward a cytotoxic response (mostly mediated by induction of a Th1 response [129 ]). To this end, microglia themselves can secrete IL-12 and IL-18, thereby providing a self-stimulating loop and activation of NK and Th1 cells [220 , 221 ]. In turn, microglia are activated and primed for phagocytosis and antigen presentation by IFN-{gamma} through expression of all receptors necessary for an adequate T cell stimulation [133 ].

IL-2, mainly involved in T cell expansion, and IL-15, a cytokine serving as a partial substitute for IL-2, can influence microglial behavior [193 ]. Both cytokines share receptors subunits, which explains their overlapping effects. IL-2 stimulates microglia by increasing their survival and NO production [133 ]. IL-15, which can also be produced by microglia themselves, selectively activates NK and CD8+ cells but has an attenuating influence on microglia [193 ]. IL-6 is an additional pleiotropic cytokine produced by microglia with pro- and anti-inflammatory properties responsible for promoting a cell-mediated humoral immune reaction (induction of Th2 response [222 ]).

On the other hand, microglia can also produce a number of anti-inflammatory cytokines, such as IL-10, TGF-β, and IL-1ra [192 , 223 , 224 ], which inhibits the actions of IL-1, and IL-10 and TGF-β down-regulate the expression of proinflammatory cytokines, ROS, chemokines, and molecules associated with phagocytosis on microglia [225 226 227 ]. In addition, Th2 cells that are able to produce IL-4 can counteract microglial activation [227 ]. It has been demonstrated that microglia can produce IL-4 and IL-13 themselves; however, autocrine stimulation seems to induce cell death [228 ]. In this context, cell loss of activated microglia might serve as an ultimate tool to prevent overactivation and increase neuronal survival [200 ].

Growth factors
GM-CSF, IL-3, and M-CSF are important inducers for microglial proliferation [82 , 133 ]. Moreover, GM-CSF stimulates free radical production by microglia [87 ] and enhances microglial phagocytosis [157 ]. In addition to their proliferation-stimulatory effect, IL-3 induces MHC class II up-regulation [229 ], and M-CSF promotes phagocytosis by microglia [158 ].

Prostanoids
PGs and thromboxanes play an important role in immune reactions. These prostanoids are potent down-regulators of microglial activation through the EP2 receptor and PPAR-{gamma} (Table 1) by inhibiting the production of proinflammatory cytokines (IL-1β [230 ]; IL-12/23/27 [207 ]; IL-18 [231 ]) and NO and the expression of MHC class II and costimulatory molecules [232 ]. Th1 cells, whose function is also down-regulated by PGE2, can supply a feedback to microglia for bursting PGE2 production [233 ]. To date, it has been shown that microglia, in vivo and/or in vitro, can express EP1, -2, -3, and -4 [230 , 234 , 235 ], but the function of these receptors (except for EP2) in microglial cell biology and their immunologic profile have yet to be elucidated.

TLR-mediated regulation of microglia
TLRs are a class of receptors that enable immune cells to recognize pathogen-associated molecular patterns (e.g., LPS, LTA, unmethylated CpG, dsRNA/DNA, peptidoglycan, and others) [236 ] but also, endogenous activators such as heat shock proteins, extracellular matrix molecules, and necrotic cells [237 ]. At least in mice, it has been demonstrated that primary cultured microglia can express TLR1–9 (of 13 known mouse TLRs) [117 ], and human microglia express TLR1–8 (of 11 known human TLRs) [42 ]. Ligation of these receptors leads to microglial expression of proinflammatory cytokines and chemokines [117 , 238 , 239 ], thereby evoking an innate immune response against viral and/or bacterial pathogens. For example, TLR2 signaling is indispensable for microglial responses against group B Streptococcus, mainly mediated by NO production [240 ]. The same receptor also evokes the production of immune molecules following in vitro infection of microglia with HSV-1 [241 ]. Moreover, TLR signaling serves as an inducer of APC functions by up-regulating MHC II and costimulatory molecules [117 ]. These TLRs also appear to be implicated in microglia homeostasis and in different neuropathologies: LPS stimulation of microglia (=TLR4-mediated) results in increased apoptosis mediated by autocrine/paracrine production of IFN-β by microglia themselves [242 ]; in a mouse model for AD, TLR4 deficiency impairs microglia to clear Aβ adequately in vitro and in vivo [243 ]; TLR2 can become up-regulated in microglia following cerebral ischemic injury, thereby mediating postischemic damage, at least in mouse CNS [244 ]. Not surprisingly, TLR-stimulated microglia can be toxic to oligodendrocytes as well as neurons in their vicinity, a consequence reported in vitro and in vivo [245 246 247 ]. Possibly, this bystander damage can be attenuated by PGs, such as 15d-PGJ2. The latter down-regulates microglial TLR2 expression and subsequent downstream effects [248 ] and thereby inhibits TLR-evoked cytokine (IL-12, TNF-{alpha}) and NO production by microglia [249 ]. PGs may thus provide a counter-regulatory feedback for TLR stimulation of microglia when aiming to balance between a beneficial versus detrimental role for these cells during neuroinflammation.

Giant cell formation
In some neuropathology conditions, e.g., AIDS-associated dementia and tuberculous meningitis, microglia acquire the highly activated phenotype of a multinucleated giant cell [250 , 251 ], and these giant cells are formed by fusion of multiple microglia, thereby producing large amounts of free radicals and proteolytical enzymes. Although the mechanism of giant cell formation still needs to be clarified further, at least this process can be affected by several cytokines and/or growth factors. IL-3, IL-4, IL-13, and GM-CSF promote the fusion of rodent microglia [252 , 253 ]. In contrast, fusion of porcine microglia is inhibited by GM-CSF [112 ] but stimulated by TNF-{alpha} [254 ].

Neuroimmune regulatory proteins
As mentioned above, microglia are kept in a quiescent state mainly through CD200–CD200R interaction, an inhibitory mechanism demonstrated to be impaired in EAE/MS [79 , 255 ], experimental autoimmune uveoretinitis [256 ], and ischemic brain injury [257 ]. At least in part, this effect is mediated by IL-4, as demonstrated by in vivo and in vitro studies [258 ]. In addition, CD47, through interaction with signal regulatory protein {alpha}, inhibits phagocytosis by macrophages [259 ] and is important in MS physiopathology [255 ]. Also, CD22, expressed and secreted by neurons, down-regulates production of proinflammatory cytokines by microglia through interaction with the CD45 surface receptor [260 ]. Scavenger receptors are another important group of surface molecules affecting microglial cell biology and function. As mentioned before, microglia are susceptible for Fas/FasL-mediated elimination, possibly by neighboring microglia with a regulatory function. Griffiths and colleagues [261 ] described neuroimmune regulation of microglia extensively.


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MICROGLIA AND CNS DISEASES
 
AD
AD is a neurodegenerative disorder characterized by three major pathological findings within the CNS: neuritic plaques (NPs) constituted mainly of β-amyloid aggregates, a degradation product of the amyloid precursor protein (APP); neurofibrillary tangles (NFTs) formed by hyperphosphorylated microtubule-associated protein {tau}; and neuroinflammation induced by (micro)gliosis. The number of NFTs correlates more with the severity of AD than the number of NPs [262 ]. However, the best correlate for the cognitive decline associated with AD is the synaptic/neuronal loss induced in part by microglia-mediated inflammatory responses [262 ]. At least in the mouse model, microglial toxicity in the AD brain appears almost directly after plaque formation and leads to further damage to the surrounding neuritic population [263 ]. Microglia in the AD-affected brain show an up-regulation of MHC class I/II, FcR, integrin, vitronectin, and scavenger receptors [264 , 265 ]. Important proinflammatory cytokines, among them IL-1, TNF-{alpha}, and IL-6, are secreted by microglia and astrocytes [266 , 267 ], further stimulating microglia to produce neurotoxins, specifically in lesioned CNS areas. These toxins comprise ROS, lipophilic amines, quinolinic acid, excitatory amino acids, and PAF and may themselves amplify glial activation responses [262 , 268 ].

Furthermore, β-amyloid or APP can activate microglia, resulting in neuronal death [268 , 269 ]. This again pinpoints microglia to be an important source for secreting neurotoxic substances. In this context, scavenger receptors and heparan sulfate, a docking site for cell binding used by apolipoprotein E (apoE), have been suggested for plaque recognition through binding of β-amyloid [268 ]. In experimental set-up, microglia have been shown to produce proinflammatory cytokines, chemokines, and ROS upon stimulation with the β-amyloid peptide (Aβ1-42) [266 , 270 ]. Moreover, proinflammatory cytokines can up-regulate APP expression, thus providing extra building stones for β-amyloid production and sustaining a vicious cycle of inflammation [271 ]. In addition, chromogranins, a group of acidic glycoproteins, are found in NPs and dystrophic neurons [272 ] and can induce microglia to produce neurotoxic products [273 ].

All complement factors needed to form the "membrane attack complex" (MAC) have been demonstrated to be present in the brain of AD patients. β-Amyloid can aggregate with the C1q protein, which in turn strongly binds the C1q receptor on microglia, leading to their activation [274 , 275 ]. In addition, the activation of complement by β-amyloid aggregates is potentiated by apoE [276 ]. In this way, the classical complement pathway is initiated without the presence of Igs. This phenomenon of microvascular β-amyloid deposition, a common pathological feature of AD, evokes an up-regulation of three complement proteins (C1q, C3, and C4) by surrounding microglia [277 ]. Eventually, the MAC will not distinguish friend from foe, leading to important neuronal loss. Although many complement inhibitors are also up-regulated in AD, these molecules probably cannot prevent the overwhelming bystander damage [278 ]. In conclusion, the inflammatory response in AD seems to be secondary to the formation of NPs and NFTs. The aggregates serve as stable irritants for microglia, leading to disease progression by a self-sustained inflammatory cycle [279 ]. This hypothesis is supported further by epidemiological and experimental animal studies using nonsteroidal, anti-inflammatory drugs, which demonstrate delayed disease onset and/or progression [280 ]. However, initially, microglial reaction can also be beneficial when aiming to clear β-amyloid by phagocytosis and secretion of proteases, e.g., neprilysin and insulin-degrading enzyme [281 ].

MS
MS is a chronic, demyelinating, inflammatory disease of the CNS with an important autoimmune component [282 ]. Without clear understanding of the events initiating MS, the pathogenesis of the lesions associated with this disease can be divided into distinct patterns. This distinction is made based on deposition of Igs and complement, location of demyelination and remyelination, and type of oligodendroglial cell death, apoptosis or necrosis [283 ]. However, all patterns and lesions have one common feature: Infiltration and activation of mostly myelin-specific T lymphocytes and myeloid cells are always found within areas of active demyelination. The contribution of microglia in MS pathogenesis remains controversial. Although microglia are able to capture, process, and present myelin as an antigen [284 ], research has not pinpointed these cells univocally as the main initiators of MS nor to its experimental counterpart EAE [285 ]. In addition, infiltration of macrophages and/or DC seems required, and microglia become activated simultaneously or subsequently as a result of immune crosstalk with infiltrating immune cells via chemokine and IL signaling [285 286 287 288 ]. In addition, a complex interplay with complement factors and/or Igs, myelin itself is able to stimulate microglia, further aggravating a microglial response by stimulating their production of neuro- and glio-toxins.

IFN-β therapy, today the most important clinical strategy to delay MS [289 ], may anticipate microglial toxicity against neurons, as shown by in vitro research [290 ]. On the other hand, microglial responses are regulated strictly by the immunosuppressive CNS microenvironment and might induce Fas/FasL-mediated apoptosis of the infiltrating, myelin-specific T cells [291 ]. In addition, it has been reported recently that microglia can suppress T cells through the programmed death receptor-1 in the EAE mouse model, thereby down-regulating Th1 cells rather than Th17 cells [292 ]. Microglia, at least in EAE, can be skewed by IL-4 to display a more beneficial activation state, devoid of neurotoxic NO production [293 ]. On the other hand, microglia associated with MS lesions, do show an elevated expression of myeloperoxidase and thus, potentially contribute to oxidative stress leading to the demyelination [294 ]. In contrast, CCR5 expressed on microglia has been reported to be associated with remyelination in MS lesions [295 ]. Although microglia themselves are not designated as initiators of MS/EAE, new, potential therapeutic agents, which act specifically by down-regulating microglial activation, do contribute to a better disease outcome in EAE [296 ]. Altogether, these reports point out a complicated role for microglia in MS/EAE: perhaps detrimental in the initial phase, responsive to the proinflammatory environment created by infiltrating T cells, but at a later stage, beneficial by clearing CNS parenchyma of T cells and myelin to control further damage and to rescue oligodendrocytes as well as neurons.

Parkinson’s disease (PD)
PD is a neurodegenerative disease typed by degeneration of dopaminergic neurons in the SN pars compacta and the loss of their projecting fibers in the striatum [297 ]. Highly elevated levels of IFN-{gamma}, TNF-{alpha}, and IL-1β are detected in the SN of PD patients. Microglia can be a source for these cytokines (Table 3) , and dopaminergic neuronal degeneration caused by activated microglia has been reported. However, especially in the case of IFN-{gamma}, in situ expression of this cytokine remains to be demonstrated. In fact, microglial activation seems an early event in PD neuropathogenesis, as shown by a gradual phagocytosis of nigral dopamine neurons by large, ramified microglia [298 ]. The activation of microglia in PD is mediated by at least three proteins released by damaged neurons: matrix metalloproteinase 3 (MMP-3), {alpha}-synuclein, and neuromelanin. MMP-3 secretion by dopaminergic neurons causes an augmented microglial production of superoxide and TNF-{alpha} [298 , 299 ]. {alpha}-Synuclein induces ROS production and secretion by microglia [300 ]. Next to toxic molecules, microglia also secrete neuroregulatory proteins upon {alpha}-synuclein stimulation, suggesting a dual response of microglia in PD [301 ], although the latter is not able to prevent PD. Neuromelanin, a dark, insoluble macromolecule that serves as an antioxidant within neurons and has neuroprotective properties through dopamine and metal binding, exerts chemotactic effects and induces microglial production of TNF-{alpha}, IL-6, and NO [302 ].

Creutzfeldt-Jacob disease (CJD)
CJD belongs to a class of transmissible spongiform encephalopathies, characterized by the deposition of protease-resistant isoforms [disease-specific prion protein (PrPSc)] of PrP [303 ]. Neuronal loss in prion diseases is mostly attributable to programmed cell death [304 ]. In vivo and in vitro models suggest that microglial activation precedes this apoptosis and is indispensable for the neurotoxicity of PrPSc [305 ]. Astrocytes and neurons recruit microglia early in prion disease through secretion of RANTES and MIP-1β. This process is CCR5-mediated, as shown by a decrease in microglial attraction by a specific CCR5 antagonist, TAK-779 [306 ]. Apparently, microglia-secreted factors (e.g., NO) consequently induce neuronal apoptosis [307 ]. In addition, PrPSc itself disables microglia to perform efficient phagocytosis of PrPSc [308 ]. Despite the fact that MHC II expression is readily up-regulated in prion disease, which is associated with the active function of microglia, CJD is classified with diseases of chronic neuroinflammation without overt T cell involvement [309 ].

Brain tumors
Infiltrative astrocytoma are characterized by the occurrence of large numbers of microglia/macrophages. One-third of all cells in glioma biopsies expresses microglial/macrophage markers [310 ]. Activated amoeboid microglia are mostly associated with high-grade tumors such as glioblastoma [311 ], and ramified microglia are found more in gemistocytic astrocytoma [312 ]. Microglia can be attracted to the tumor site by chemokines (e.g., MCP-1) and growth factors (e.g., CSF-1 and G-CSF), locally produced by tumorigenic astrocytes [313 314 315 ]. In addition, these growth factors contribute to proliferation of microglia within astrocytoma.

Despite their presence, immune function of microglia in astrocytoma is likely to be suppressed. Although they are relatively abundant, the number of MHC class II expressing microglia is reduced in high-grade astrocytic gliomas [316 ]. Indeed, it has been shown that tumor-associated microglia fail to express MHC II upon stimulation [317 ]. Glioma culture supernatants can suppress IFN-{gamma}-induced MHC-II expression on microglial cells, thereby impairing their ability for proper antigen presentation and thus, preventing the induction of an efficient anti-tumor immune response [318 ]. Brain tumors can also produce anti-inflammatory cytokines, e.g., IL-6 and TGF-β, which potently down-regulate microglial immune-effector functions [319 ]. This immunosuppressive environment is enhanced further via IL-10 production by microglia themselves [320 ]. The latter cytokine is up-regulated in microglia by a tumor-associated, lower expression of upstream stimulating factor-1 [321 ]. Even more, IL-6 and IL-10 have been associated with tumor growth and infiltration [322 , 323 ]. To this extent, microglia secrete endothelial growth factor (EGF), vascular EGF (VEGF), and hepatocyte growth factor (HGF) in brain tumors, all of which are associated with cell growth, metastasis, and angiogenesis [324 ].

HIV-associated neuropathology
Entry of HIV in the CNS is actively mediated via microglia or perivascular macrophage infection, and neurons and other glia are not likely to be active carriers. How HIV might infect microglia remains elusive, as they do not express detectable levels of the CD4 receptor. Antibody-mediated uptake of virus via FcRs expressed at the microglial cell surface has been suggested as an alternative mechanism for HIV infection [325 ], although the chemokine receptor CCR5, also expressed by microglia, is currently considered as the most important "gate" for viral entrance [326 ]. However, others question microglia as a source of viral reproduction and ascribe sustained infection of the CNS to perivascular macrophages, which are replenished continuously by HIV-infected peripheral blood monocytes [327 ].

HIV-associated dementia (HAD) has been correlated with activation of microglia and macrophages in brain tissue. The latter is the major cause of neuronal damage or loss within the CNS following HIV infection [328 ]. A typical hallmark of HAD is multinucleated giant cell (MNGC) formation. These cells originate from the fusion of microglia and/or macrophages to become a highly activated cell. MNGC produce excessive amounts of ROS, enzymes, but also viral proteins [329 , 330 ]. Among the latter, viral HIV-I Tat, gp120, and Vpr can act as direct neurotoxic substances or add to the bystander damage by further stimulating inflammation [331 ]. This innate and viral neurotoxic cocktail, together with the production of ILs and chemokines, which attract even more inflammatory cells, is suggested to account for the major neuronal loss associated with HAD.

Miscellaneous neuropathology-associated stimuli for microglial activation
The main cause of encephalitis or meningitis (for a review, see ref. [332 ]) includes viruses such as HIV, varicella zoster virus, human herpes viruses 6 and 7, EBV, cytomegalovirus, enteroviruses, adenoviruses, and influenza virus A/B. However, bacteria, rickettsiae, fungi, and protozoae are also potential intruders of the CNS. Major consequences of infection might include edema, hemorrhage, brain abscess, demyelination, neuronophagy, and necrosis, dependent on the source of infectious material. In response to all of these infections, microglia become activated and might produce a number of proinflammatory cytokines and chemokines, up-regulate phagocytosis and ROS production, and even serve as a reservoir.

Microglia are the first immune cells to sense damage to the CNS caused by a traumatic injury, upon which they react by increased expression of excitatory amino acid transporters (EAAT). Injury-associated cortical cell loss and concomitant increase in excitatory amino acids add to secondary brain damage, whereas microglia perhaps try to compensate for these events with a potential neuroprotective response [333 ]. Another type of cerebral injury occurs during ischemia or stroke. Hereby, microglia are stimulated to produce a broad spectrum of immune molecules. Synthesis and release of complement factor C1q by microglia are highly increased upon ischemic injury [334 ]. Neuronal secretion of fractalkine and MCP-1 is up-regulated in response to ischemia, whereas microglia produce increased levels of MIP-1{alpha} and MIP-2 [335 336 337 ]. Simultaneously, the expression of chemokine receptors CCR5 and the fractalkine receptor CX3CR1 on a microglial surface is increased [335 , 336 ]. Following ischemia, microglia display elevated production of potentially neurotoxic IL-1β and TNF-{alpha} and TNFR1/2 [338 , 339 ]. IL-6 is produced by microglia after ischemia, although this expression returns to basal level a few hours post-insult [340 ]. In ischemic events, this cytokine and its close relative ciliary neurotrophic factor decrease neuronal death [341 , 342 ]. Platelet-derived growth factor and glial cell line-derived neurotrophic factor are two neurotrophic factors produced by post-ischemic microglia able to promote neuronal survival [343 , 344 ]. The anti-inflammatory cytokine TGF-β, secreted by microglia after ischemia, can also promote neuronal survival directly or have an autocrine/paracrine influence in which microglial overactivation and secondary neuronal damage are prevented [345 ]. Analogously to traumatic brain injury, microglia can up-regulate EAAT to scavenge glutamate and may reduce its neurotoxic potential [345 ]. However, it should be mentioned that microglia (in contrast with astrocytes), despite their expression of EAAT, are not capable of reducing the neurotoxicity of glutamate in vitro [346 ]. In conclusion, microglia also have been demonstrated to produce several neurotrophins (NTs; e.g., brain-derived neurotrophic factor, nerve growth factor, NT-3/4/5) and/or growth factors (e.g., insulin-like growth factor-1, basic fibroblast growth factor, HGF, VEGF, EGF) potentially beneficial to neuronal survival [145 ].


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EXPERIMENTAL MODELS FOR MICROGLIA RESEARCH IN VITRO AND IN VIVO
 
Throughout literature, in vitro culture models for microglia are usually based on the same methodology, although variations may exist to investigate different aspects of microglial cell biology or to simulate different neuropathological disease conditions. The short overview below briefly describes current possibilities for studying microglia in vitro.

Microglia can be obtained from mixed cortical glial cultures originating from embryonic/fetal, adult, or diseased CNS of different species (rat [35 ]; swine [160 ]; human [266 ]; goldfish [347 ]; quail [348 ]). These cultures are started as a monolayer, mainly consisting of astrocytes with few contaminating fibroblasts, endothelial cells, and oligodendrocytes. After 2 weeks, confluence is reached, and loosely adherent microglia proliferate actively on top of the astrocyte feeder layer. Their proliferation is stimulated mainly by growth factors (e.g., GM-CSF, CSF-1), produced by this feeder layer, and microglia can be recovered by shaking the culture plate. The main challenge of this culture model is to reinduce the ramified morphology of microglia, which is usually lost by activation during tissue preparation. At least in vitro, this can be established by adding growth factors (e.g., GM-CSF [87 ]) or through direct contact with an epithelial monolayer [82 ]. Although most experiments are performed using primary microglia cultures, a few microglial cell lines have been described. Although BV-2 and N9 mouse microglial cell lines [349 ] are well described in literature, laboratory-specific microglia cell lines also exist [350 ]. In addition, an important organotypic model for microglia research is the retina [351 ]. This can be removed without contaminating tissue and allows surveyable analysis of ramified microglia in situ. The organotypic brain slice preparation [36 ] has been proposed as an alternative for whole mount culture. However, like mostly observed during microglial monoculture, microglia might acquire an activated state as a result of manipulation and culture conditions.

Throughout literature, several animal models for microglia research have been well characterized and are discussed partially within this review. Table 4 provides an overview of several in vivo research models, which might serve as a basis for in vivo microglia research in neuropathology.


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  		Table 4. Models for Microglia in Neuropathology


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CONCLUDING REMARKS
 
As a result of their versatile phenotype and the lack of appropriate biomarkers, microglia were often misidentified in the past. However, nowadays, microglia can be distinguished clearly from other CNS populations using an extensive "microglia-defining" set of molecules together with their highly specialized immunologic function. Moreover, it is clear now that microglia are involved in virtually all neuropathological processes. Within inflamed CNS (e.g., infections, autoimmune diseases), they can cause primary damage to neurons, and in neurodegenerative disease (e.g., AD, PD), microglia become highly reactive to dying neuronal cells and provoke secondary neurotoxicity. Therefore, the research aim for neuroscientists and immunologists has now shifted toward investigating the balance of a "beneficial" versus a "detrimental" phenotype of microglia in the CNS tissue. On the one hand, they can display "good guy" characteristics by producing neurotrophic growth factors and clear endogenous and exogenous neurotoxins (e.g., excitatory amino acids) and eliminate unwanted inflammatory cells (e.g., autoreactive T cells) from the nervous parenchyma. On the other hand, they can aggravate CNS injury by production of neuro- and/or gliotoxins (e.g., ROS, NO, enzymes) and thus cause a sustained, vicious cycle of microglial activation with subsequent secondary neural damage. However, it should be kept in mind that microglial actions are controlled by several neuroimmune regulatory mechanisms and are adapted to the CNS environment. Indeed, compared with its peripheral counterpart (i.e., macrophages), microglia seem to be restricted and/or limited in their immune functions, although their capacity to proliferate in situ might increase their power instantaneously. Perhaps these characteristics allow them to screen and protect the CNS in a gentle, neuron-friendly manner.

Received June 26, 2008; revised October 23, 2008; accepted October 27, 2008.


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