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Cellular forms and functions of brain microglia
Brain ResearchBulletin,Vol. 34, No. 1, pp. 73-78, 1994 Copyright0 1994Elsevier ScienceLtd Printed in the USA. All n&us reserved 0~~-9~~4 $6.08 + .oo
Pergamon 0361-9230(93)Eoo43-L
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 transplantation, and AIDS dementia complex, as well as many other neurological mechanisms and diseases. Monocytes Ramified microglia Immune mechanisms
Amoeboid microglia
Reactive microglia
Macrophages
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 array (2663). Ramified microglia have been characterized as highly downregulated or inactive macrophages, as they lack most corresponding markers and activites of this cell group. However, the ramified 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 microglia arise from monocytic blood cells (5,6,34,54,55). This is consistent with the unifying hypothesis of the mononuclear phagocyte system (70) which indicates that all macrophages come from blood monocytes derived from the bone marrow. Monocytes migrate into the fetal tissue prior to and during the development 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, monocytes convert into ramified cells through an intermediate form called the amoeboid microglia. The amoeboid cell form possesses 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 precursors of the ramitied microglial form (2,19,35,54). Thus, the ramified microglia in adult brain appear to be derived develop-
central nervous system (CNS) has been as highly debated with regard to its functional properties as microglial cells. These cells were originally identified and characterized by de1 Rio-Hortega (12) yet their functional 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 attributes using many different experimental approaches and, in addition 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 microglia). These ramified cells display a striking mo~hological appearance (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.
NO other cell type of the mammalian
’ To whom requests for reprints should be addressed. 73
DAVIS,
FOSTER
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 express 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 different morphological forms are correlates of a sequential upregulation 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 morphological states in a progressive fashion which are termed activated and reactive microglia, respectively (64). Activated microglia 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 morphologies; all lack ramified-type processes (1,868). Activated mi-
AND
THOMAS
peroxidase-conjugated
croglial cells appear to be practically active macrophages, as they express CR3 complement receptors (30) and class I major histocompatibility 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 microglia to active macrohages occurs in a sequential or stepwise manner involving a transition from ramified cell to activated microglia to reactive microglia. Also, there is a consistent correlation 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 upregulate 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 microglial 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 corresponding 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
Amoehoid Mirrqlia
0++
7s
CELLS
Randfied (resting) hlicroglin
0--
Blood Monocytes
Activated Microglir
0+-
Reactive Microglia
0++
Gianl Multi-nucleated Cell
FIG. 2. Diagram depicting the sequential cellular forms and corresponding level of macrophage activity comprising the life cycle of brain microgfia. Drawings are not to scale: see text for details.
rived through fusion of reactive cells (48,49). Giant multinucleated 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 infectious 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 demonstrated in this specific cell. Thus, it is not known if giant multinucleated 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 functional 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 connectivity 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 tissues. However, this downre~lation is consistent with the concept of immune privilege and the specific need to protect this differentially sensitive tissue from consequent immune-mediated
cellular damage. Another unique feature is the apparent permanency 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 infiltration 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 infiltration, as well as to replace spent or exhausted cells and maintain a constant population size, intrinsic mitotic activity is required. While microglial cells present several unique properties as macrophages, in light of the ideas discussed above, these properties 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 functional 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
DAVIS,
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 automatically assumed. The microglia are an intriguing cell population that have recently begun to receive more attention in experimental investigation. This attention is justified by their role as brain macrophages 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 suggested to serve a constitutive function. While ramified microglia were generally considered inactive macrophages and only of significance 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 immune responses, rejection of transplanted tissue, and AIDS-associated dementia complex. Macrophages are an integral component 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 lymphocyte 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
FOSTER
AND THOMAS
(59,60). Hence, microglial cells may serve a vital part of immune responses in the CNS. Recognition of transplanted tissue as foreign and subsequent rejection in graft-vs.-host disease is essentially an immune response mechanism. Microglia have been suggested to be a major component of tissue rejection for cells and tissue transplanted into brain (16,33,44,56,61). Finally, AIDS disease is frequently accompanied by a specific dementia complex (57). The HIV-l virus selectively infects microglia in brain tissue (42,43,71,73). While it has been suggested that AIDS dementia complex is due to a loss of neurons (40), possibly as a result of neurotoxins derived from microglia (23,46), it has not been completely eliminated that infection and debilitation of microglia themselves may, at least in part, contribute to the symptoms of the dementia. The exact basis of AIDS dementia is still an unresolved issue; however, microglia must play a central role because they are the infected cells. In concluding, based on functional properties and the tissue processes which microglia appear to be involved in, these cells have emerged as a significant population in brain tissue. While much information relative to microglial cells has recently been revealed, it is hoped that these cells will continue to receive increasing attention and that further insight to their functional mechanisms will be provided in the future.
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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Pergamon 0361-9230(93)Eoo43-L
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 transplantation, and AIDS dementia complex, as well as many other neurological mechanisms and diseases. Monocytes Ramified microglia Immune mechanisms
Amoeboid microglia
Reactive microglia
Macrophages
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 array (2663). Ramified microglia have been characterized as highly downregulated or inactive macrophages, as they lack most corresponding markers and activites of this cell group. However, the ramified 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 microglia arise from monocytic blood cells (5,6,34,54,55). This is consistent with the unifying hypothesis of the mononuclear phagocyte system (70) which indicates that all macrophages come from blood monocytes derived from the bone marrow. Monocytes migrate into the fetal tissue prior to and during the development 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, monocytes convert into ramified cells through an intermediate form called the amoeboid microglia. The amoeboid cell form possesses 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 precursors of the ramitied microglial form (2,19,35,54). Thus, the ramified microglia in adult brain appear to be derived develop-
central nervous system (CNS) has been as highly debated with regard to its functional properties as microglial cells. These cells were originally identified and characterized by de1 Rio-Hortega (12) yet their functional 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 attributes using many different experimental approaches and, in addition 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 microglia). These ramified cells display a striking mo~hological appearance (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.
NO other cell type of the mammalian
’ To whom requests for reprints should be addressed. 73
DAVIS,
FOSTER
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 express 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 different morphological forms are correlates of a sequential upregulation 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 morphological states in a progressive fashion which are termed activated and reactive microglia, respectively (64). Activated microglia 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 morphologies; all lack ramified-type processes (1,868). Activated mi-
AND
THOMAS
peroxidase-conjugated
croglial cells appear to be practically active macrophages, as they express CR3 complement receptors (30) and class I major histocompatibility 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 microglia to active macrohages occurs in a sequential or stepwise manner involving a transition from ramified cell to activated microglia to reactive microglia. Also, there is a consistent correlation 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 upregulate 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 microglial 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 corresponding 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
Amoehoid Mirrqlia
0++
7s
CELLS
Randfied (resting) hlicroglin
0--
Blood Monocytes
Activated Microglir
0+-
Reactive Microglia
0++
Gianl Multi-nucleated Cell
FIG. 2. Diagram depicting the sequential cellular forms and corresponding level of macrophage activity comprising the life cycle of brain microgfia. Drawings are not to scale: see text for details.
rived through fusion of reactive cells (48,49). Giant multinucleated 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 infectious 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 demonstrated in this specific cell. Thus, it is not known if giant multinucleated 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 functional 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 connectivity 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 tissues. However, this downre~lation is consistent with the concept of immune privilege and the specific need to protect this differentially sensitive tissue from consequent immune-mediated
cellular damage. Another unique feature is the apparent permanency 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 infiltration 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 infiltration, as well as to replace spent or exhausted cells and maintain a constant population size, intrinsic mitotic activity is required. While microglial cells present several unique properties as macrophages, in light of the ideas discussed above, these properties 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 functional 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
DAVIS,
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 automatically assumed. The microglia are an intriguing cell population that have recently begun to receive more attention in experimental investigation. This attention is justified by their role as brain macrophages 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 suggested to serve a constitutive function. While ramified microglia were generally considered inactive macrophages and only of significance 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 immune responses, rejection of transplanted tissue, and AIDS-associated dementia complex. Macrophages are an integral component 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 lymphocyte 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
FOSTER
AND THOMAS
(59,60). Hence, microglial cells may serve a vital part of immune responses in the CNS. Recognition of transplanted tissue as foreign and subsequent rejection in graft-vs.-host disease is essentially an immune response mechanism. Microglia have been suggested to be a major component of tissue rejection for cells and tissue transplanted into brain (16,33,44,56,61). Finally, AIDS disease is frequently accompanied by a specific dementia complex (57). The HIV-l virus selectively infects microglia in brain tissue (42,43,71,73). While it has been suggested that AIDS dementia complex is due to a loss of neurons (40), possibly as a result of neurotoxins derived from microglia (23,46), it has not been completely eliminated that infection and debilitation of microglia themselves may, at least in part, contribute to the symptoms of the dementia. The exact basis of AIDS dementia is still an unresolved issue; however, microglia must play a central role because they are the infected cells. In concluding, based on functional properties and the tissue processes which microglia appear to be involved in, these cells have emerged as a significant population in brain tissue. While much information relative to microglial cells has recently been revealed, it is hoped that these cells will continue to receive increasing attention and that further insight to their functional mechanisms will be provided in the future.
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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