Brain ResearchBulletin,Vol. 34, No. 1, pp.

73-78, 1994
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REVIEW

Cellular Forms and Functions of Brain Microglia

E. J. DAVIS, T. D. FOSTER AND W. E. ~0~s’

Department of Biology, Howard University, 415 College St. NW, Washington, DC 20059

Received 9 September 1993; Accepted 30 November 1993

DAVIS, E. J., T. D. FOSTER AND W. E. THOMAS. Cetluiur forms a~~~ctio~ of brain microglia. BRAIN RBS BULL 34(l)
73-78, 1994.-Consistent with the recent characterization of microglial cells as macrophages, an overall picture for the unique
function of these cells in CNS tissue has developed. The microglia are derived from blood monocytes that migrate into the tissue
during fetal development and subsequently remain after complete formation of the blood-brain barrier. These monocytes give
rise to the ramified microglia of adult tissue through the developmental intermediate of amoeboid microglia. Ramified microglia
appear uniquely adapted in contrast to other tissue macrophages based on their stability or lack of turnover and mitotic capability.
The ramified cells, while usually downregulated, can convert into active macrophages termed reactive microglia; this conversion
appears to occur nons~cifically in response to any injury. Further, reactive microglial cells can fuse to form giant mult~ucleated
cells during viral infections. Each microglial ceil form possesses a characteristic morphology and differing functional state with
regard to macrophage activity. In their role as tissue macrophages, microglia are involved in immune responses, tissue transplan-
tation, and AIDS dementia complex, as well as many other neurological mechanisms and diseases.

Monocytes Ramified microglia Amoeboid microglia Reactive microglia Macrophages

Immune mechanisms

NO other cell type of the mammalian central nervous system
(CNS) has been as highly debated with regard to its functional
properties as microglial cells. These cells were originally iden-
tified and characterized by de1 Rio-Hortega (12) yet their func-
tional significance remained unclear until possibly the last 5 to
10 years. Very recent work suggests that they serve as tissue
resident macrophages within the CNS [reviewed in (14,27,39)].
This work involves an assessment of several macrophage attri-
butes using many different experimental approaches and, in ad-
dition to supporting this proposed cellular identity, it also appears
to reveal a very interesting story on the life history or cellular
cycle of these ceils. The life cycle of microglial cells is the subject
of this brief discussion; these cells appear to be characterized by
multiple morphological and functional states uniquely adapted
for the environment of CNS tissue. The different states provide
a distinctive picture for CNS macrophages in comparison to those
of other tissues and provide the basis for their apparent life cycle.
The cellular form of microglia present in normal adult brain
has been termed ramified microgha (also called resting microg-
lia). These ramified cells display a striking mo~hological ap-
pearance (see Fig. 1). They possess a small (5- 10 pm) oval cell
body and the nucleus usually fills most of the soma leaving a
very small volume of cytoplasm (7,54,67,69). Radiating from the
soma are numerous processes of small diameter; these processes
typically extend several times the diameter of the cell body in
length, often branch, and usually exhibit a rough or spiny surface.
With this unique appearance, the cells correspond to S-15% of
the total cellular composition of brain tissue, and they are evenly
distributed throughout the CNS, forming a somewhat regular ar-
ray (2663).
Ramified microglia have been characterized as highly down-
regulated or inactive macrophages, as they lack most correspond-
ing markers and activites of this cell group. However, the rami-
fied cell form is thought to be derived from and capable of
conversion into active macrophages (Fig. 2). In terms of cellular
origin, the prevailing view from contemporary studies is that mi-
croglia arise from monocytic blood cells (5,6,34,54,55). This is
consistent with the unifying hypothesis of the mononuclear phag-
ocyte system (70) which indicates that all macrophages come
from blood monocytes derived from the bone marrow. Mono-
cytes migrate into the fetal tissue prior to and during the devel-
opment of the blood-brain barrier (10,11,50); the cells become
trapped with complete formation of the barrier and remain as
permanent residents. Within the developing brain tissue, mono-
cytes convert into ramified cells through an intermediate form
called the amoeboid microglia. The amoeboid cell form pos-
sesses a broad, flat morphology often exhibiting pseudopodia
(36,45). Amoeboid microglia are a transient population present
during the late prenatal to early postnatal period (37,38,52), and
there is reasonable evidence that these cells are the direct pre-
cursors of the ramitied microglial form (2,19,35,54). Thus, the
ramified microglia in adult brain appear to be derived develop-

’ To whom requests for reprints should be addressed.

73

FIG. 1. Individual ramified microglial cells in rat cerebral cortex are shown in A and B. Cells are stained with horseradish
Gri,@ia simplicifoliaisolectin according to the method of Streit (63). Magnification: X 1000, scale bar = 10 pm for both.
mentally from sequential conversion of monocytes to amoeboid
microglia to ramified microglia.
As stated, the ramified cells are downregulated; however,
monocytes and the amoeboid microglia exhibit differing levels
of expression of macrophage activity. Monocytes typically ex-
press partial macrophage function, while the amoeboid cells are
fully active macrophages. Phagocytic amoeboid cells appear to
remove redundant or inappropriate neuronal processes (41) and
cellular debris from natural neuronal cell death (15,35), as well
as serving a role in the regulation of gliogenesis (24). Hence, in
the maturation or differentiation of ramified microglia, the dif-
ferent morphological forms are correlates of a sequential upreg-
ulation and downregulation in macrophage functional state. The
signalling mechanisms regulating these alterations in expression
are unknown.
The downregulated ramified cells of adult tissue are capable
of conversion into active macrophages, i.e., upregulation. This
conversion also is accompanied by at least two different mor-
phological states in a progressive fashion which are termed ac-
tivated and reactive microglia, respectively (64). Activated mi-
croglia appear like swollen ramified cells and are characterized
by a larger cell body with shorter, stouter processes (29,67). The
reactive microglia are typically small, spherical cells, but can also
exhibit rod-shaped and pleomorphic or amoeboid-like morphol-
ogies; all lack ramified-type processes (1,868). Activated mi-
DAVIS, FOSTER AND THOMAS
peroxidase-conjugated
croglial cells appear to be practically active macrophages, as they
express CR3 complement receptors (30) and class I major his-
tocompatibility complex (MHC) antigen (65,66). Reactive cells
are fully active macrophages with increased CR3 receptor and
class I MHC (28,64), and expressing class II MHC (28,66) and
phagocytic activity (68). Thus, the conversion of ramified mi-
croglia to active macrohages occurs in a sequential or stepwise
manner involving a transition from ramified cell to activated mi-
croglia to reactive microglia. Also, there is a consistent correla-
tion of morphology with functional state. Once again, the specific
signals that regulate the expression of macrophage properties are
unclear; however, ramified microglia appear to activate or up-
regulate in response to all types of tissue damage
(1,21,47,62,64,66). The exact functional role of the activated
cells other than as precursors for active macrophages is uncertain,
although they may serve in immune mechanisms (see below);
however, among the most significant functions of reactive mi-
croglial macrophages is phagocytosis-to remove debris and
foreign substances. Reactive cells have also been indicated to
regulate astrogliosis in scar formation (20,22) in a similar manner
as astrogliogenesis during development.
Finally, another microglial form has been identified corre-
sponding to a giant multinucleated cell (13). As its name implies,
this cell form is much larger than the other microglial forms; it
has an overall amoeboid-type morphology and appears to be de-
LIFE CYCLE OF MICROGLIAL CELLS
Amoehoid Randfied (resting)
Mirrqlia hlicroglin
0++ 0--
Blood
Monocytes
FIG. 2. Diagram depicting the sequential cellular forms and corresponding level of macrophage activity com-
prising the life cycle of brain microgfia. Drawings are not to scale: see text for details.
rived through fusion of reactive cells (48,49). Giant multinucle-
ated cells are associated with various types of viral infections in
brain, most notably HIV-1 (14). In fact, these large microglia are
considered a hallmark of acquired immune deficiencey syndrome
(AIDS) encephalitis (9). Whether this cell form can occur in the
absence of viral infection is uncertain; there have been few or no
reports of giant multinucleated cells without a precipitating in-
fectious agent. The mechanism of microglial cell fusion as well
as why and how it is induced by HIV-l or other viruses are
similarly unwon. In addition, the functional significance of this
form is unclear. While it is tempting to draw a comparison to
multinucleated macrophages in other tissues, active macrophage
properties, particularly phagocytosis, have not been demon-
strated in this specific cell. Thus, it is not known if giant multi-
nucleated microglia are active macrophages or rather a collection
of exhausted reactive microglia or even a totally abnormal form
with no direct ~n~ional role.
Overall, microglia exhibit multiple mo~hologic~ and func-
tional states, providing a view of a life cycle consistent with their
role as CNS macrophages (Fig. 2). Several aspects of this life
cycle reflect unique adaptations for the CNS environment. While
all tissue macrophages are thought to originate from monocytes,
microglia are unique in the possession of an active macrophage
~te~ediate (amoe~id cells). However, brain tissue has a much
higher level of embryonic cell death than most other tissues.
Also, the need for specificity of cellular interactions and connec-
tivity is much greater than in other tissues. Thus, phagocytic
amoeboid microglia may be a select developmental requirement
of CNS histogenesis. The downregulated nature of microglia in
adult tissue (ramified cells) and subsequent upregulation when
macrophages are needed contrasts with macrophages in other tis-
sues. However, this downre~lation is consistent with the con-
cept of immune privilege and the specific need to protect this
differentially sensitive tissue from consequent immune-mediated
7s
Activated Reactive
Microglir Microglia
0+- 0++
Gianl
Multi-nucleated
Cell
cellular damage. Another unique feature is the apparent perma-
nency or stable nature of ramified microglia in adult tissue, as
there appears to be little or no turnover of these cells. Resident
macrophages in other tissues undergo constant turnover as they
are replaced by new cells derived from monocytes (3). The fact
that microglia remain a permanent population apparently
throughout adult life under normal circumstances may, at least
in part, be attributed to the presence of the blood-brain barrier
and the lack of access of this tissue to routine monocyte infiltra-
tion from the blood. A final differential property of microglia
compared to other macrophages is that they appear capable of
significant proliferation (19,26,31). This feature seems to go hand
in hand with their stable nature. To be able to increase the overall
amount of macrophage activity in the absence of monocytic in-
filtration, as well as to replace spent or exhausted cells and main-
tain a constant population size, intrinsic mitotic activity is re-
quired. While microglial cells present several unique properties
as macrophages, in light of the ideas discussed above, these prop-
erties are a reflection of their specific location in CNS tissue.
Microglia are clearly a unique component of brain tissue and
are also relatively unique as macrophages. The purpose of the
present description was to try to provide an overview of the func-
tional properties and life cycle of microglial macrophages. The
area of brain macrophages has been complicated by a massive
amount of confusing studies. It is hoped that this description will
provide insight to facilitate the interpretation of previous work
and contribute to pointing out direction for future investigation.
In addition, it should also serve as somewhat of a precautionary
note relative to a broad variety of neuroscience research. Because
microglia appear to exhibit nonspecific upregulation in response
to tissue damage, any ex~rimental technique or disease state
involving injury should induce their activation. This activation
becomes more pronounced and widespread with more severe or
progressed injury (64). Thus, microglial activation and subse-
76
quent tissue effects may be encountered in many situations. Also,
by the same token, a specific involvement of microglia or even
immune function under certain conditions can not be automati-
cally assumed.
The microglia are an intriguing cell population that have re-
cently begun to receive more attention in experimental investi-
gation. This attention is justified by their role as brain macro-
phages and a function in cellular debris removal and astrogliosis,
both in developing and adult tissue. These activities are supported
for the active macrophage cellular forms; however, the ramified
or resting microglia (inactive macrophages) have also been sug-
gested to serve a constitutive function. While ramified microglia
were generally considered inactive macrophages and only of sig-
nificance as precursors for active macrophages, it has recently
been suggested that this form may function in extracellular fluid
cleansing and transmitter inactivation, especially for diffusible
neurotransmitters/neuromodulators in volume transmission
(4,25,58,72). Further support for this hypothesis is derived from
the close association of these cells with neurons and synapses
(5153). Thus, microglia may contribute to the normal operation
of brain tissue.
In addition to the functional attributes of above, microglia
appear to be involved in several other processes, including im-
mune responses, rejection of transplanted tissue, and AIDS-as-
sociated dementia complex. Macrophages are an integral com-
ponent of the immune response in other tissues and contribute to
the generation of this response through antigen presentation and
lymphocyte activation, and the coordinated regulation of lym-
phocyte activity by cytokine secretion. Activated or upregulated
microglia have been indicated to be capable of antigen-mediated
lymphocyte activation (18,34), and to secrete interleukin-1
(20,32), interleukin-6 (1759) and tumor necrosis factor-alpha
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ACKNOWLEDGEMENTS
The expert assistance of Ms. J. B. Sonceau in the preparation of the
manuscript is greatly appreciated; gratitude is also expressed to Mr. Ken
Marshburn and Chroma Studios for production of color photographs, and
to Mr. H. J. Wynder for black-and-white photography. The authors are
supported by the National Science Foundation (BNS-9114085) and the
Faculty Research Support Grant Program of Howard University.
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