Microglia, the only nonneuroepithelial cells found in the parenchyma of the CNS, originate during embryogenesis from the yolk sac and enter the CNS quite early (embryonic day 9.5–10 in mice). Thereafter, microglia are maintained independently of any input from the blood and, in particular, do not require hematopoietic stem cells as a source of replacement for senescent cells. Monocytes are hematopoietic cells, derived from bone marrow. The ontogeny of microglia and monocytes is important for understanding CNS pathologies. Microglial functions are distinct from those of blood-derived monocytes, which invade the CNS only under pathological conditions. Recent data reveal that microglia play an important role in managing neuronal cell death, neurogenesis, and synaptic interactions. In this article, we discuss the physiology of microglia and the functions of monocytes in CNS pathology. We address the roles of microglia and monocytes in neurodegenerative diseases as an example of CNS pathology.

Microglia are resident mononuclear phagocytes in the CNS that are traditionally considered to be involved mainly in immune responses and inflammatory diseases. Perivascular, choroid plexus, and meningeal macrophages, monocyte-derived cells, are also phagocytic cells in the CNS and have, at times, been referred to as either macrophages or microglia, without specifically addressing their origin. Over the past two decades, research on brain myeloid cells has been markedly improved by the advent of new tools in imaging, genetics, and immunology and has opened up a new era in understanding and treating CNS pathologies.

Recent studies revealed that microglia are the only myeloid cells found in the healthy CNS parenchyma. Microglia and monocyte-derived cells are distinct by their ontogeny, physiology, and response to environmental changes. When the CNS is inflamed, all of the microglia and monocyte-derived cells can give rise to macrophages, as defined by morphology and surface staining, yet the functions of individual macrophages may differ radically, according to their ontogeny. Understanding macrophage ontogeny and functions will help to determine potential roles of modulating microglial activation and monocyte infiltration in disease treatment.

Monocytes are blood mononuclear cells and are renewed continually from bone marrow hematopoietic stem cells throughout life. During postnatal life, myeloid progenitor cells in the bone marrow give rise to common monocyte–dendritic cell progenitors, which, in turn, yield blood monocytes and dendritic cell progenitors. Tissue macrophages can be derived early in development from yolk sac–primitive macrophages and, subsequently, from blood monocytes and circulating mononuclear phagocyte progenitors. Tissue macrophages are maintained either by local self-renewal or by influx of cells from the circulation (1). In mice, hematopoietic cells appear within the hematogenic endothelium of the aorta–gonado–mesonephros region at embryonic day (E)10.5 (2) and migrate to the fetal liver, where they expand and differentiate starting at E12.5 (3). The transcription factor Myb is required for the development of hematopoietic stem cells and all CD11bhigh monocytes and macrophages, but it is dispensable for yolk sac macrophages and for the development of yolk sac–derived F4/80bright macrophages in several tissues, such as liver Kupffer cells, epidermal Langerhans cells, and microglia cell populations that are Pu.1 dependent (4) (Fig. 1).

FIGURE 1.

(A) Microglia and monocyte ontogeny and their characteristics. Microglia are derived from primitive macrophages in a Myb-independent manner via PU.1- and IRF8- dependent pathways. This lineage is primarily regulated by CSF-1R, its ligand IL-34, and TGF-β. Microglia are maintained independently of circulating monocytes throughout life. In the steady-state, apoptotic neurons expressing “eat me” signals are removed by ramified microglia. Ramified microglia are also an essential component of neurogenesis and synapse maintenance. Microglial insulin-like growth factor 1 and BDNF are key mediators of synaptic plasticity. In response to tissue damage, DAMPs are released and cause microglia to release of neurotoxic factors from microglia. (B) Monocytes are derived from hematopoietic stem cells appear at E 10.5. Transcription factor Myb is required for development. Human CD14+ macrophages have several spectra of activation signatures, depending on the stimulus. Partly modified from the graphical abstract in Xue, J., et al. (48).

FIGURE 1.

(A) Microglia and monocyte ontogeny and their characteristics. Microglia are derived from primitive macrophages in a Myb-independent manner via PU.1- and IRF8- dependent pathways. This lineage is primarily regulated by CSF-1R, its ligand IL-34, and TGF-β. Microglia are maintained independently of circulating monocytes throughout life. In the steady-state, apoptotic neurons expressing “eat me” signals are removed by ramified microglia. Ramified microglia are also an essential component of neurogenesis and synapse maintenance. Microglial insulin-like growth factor 1 and BDNF are key mediators of synaptic plasticity. In response to tissue damage, DAMPs are released and cause microglia to release of neurotoxic factors from microglia. (B) Monocytes are derived from hematopoietic stem cells appear at E 10.5. Transcription factor Myb is required for development. Human CD14+ macrophages have several spectra of activation signatures, depending on the stimulus. Partly modified from the graphical abstract in Xue, J., et al. (48).

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Microglial origin and developmental lineage were controversial, and a consensus about microglial ontogeny was reached only recently. According to one view, microglia were thought to originate from a neuroepithelial precursor, whereas other investigators proposed that meningeal macrophages penetrated the brain during embryonic development, when they were first isolated from leech CNS preparations in 1920. Later, in the 1990s, postnatal and adult microglia were proposed to be derived from blood-borne monocytes (5).

It is now recognized that the late-embryonic and adult mouse brain parenchyma contain microglial progenitors (6), which have been detected in the brain rudiment from E8, after their appearance in the yolk sac (7). It was established in the late 1990s that microglia were not epithelial, using mice that lack the transcriptional factor PU.1 (PU.1−/− mice), which is expressed exclusively in cells of the hematopoietic lineage (8). PU.1−/− mice lack microglia in the CNS, as well as the myeloid lineage and B cells and T cells. In vivo lineage-tracing studies also showed that adult microglia derive from primitive myeloid progenitors that arise embryonically, mainly between E7.0 and E7.5, and that they are highly proliferative throughout embryonic life (9). Moreover, it was shown that postnatal hematopoietic progenitors do not contribute to microglial homeostasis in the adult mouse brain, using irradiated newborns with hematopoietic cells isolated from congenic mice, adult congenic bone marrow chimera models, and parabiotic mice (9). Postnatal microglia are maintained independently of circulating monocytes throughout life (10), and dying microglia are replaced entirely from cells that colonize the brain before birth. It remains uncertain whether new microglia arise by asymmetric division from an uncharacterized progenitor or by symmetric division from another microglial cell. In addition, during experimental autoimmune encephalomyelitis in which hematopoietic cells infiltrate the CNS, their presence is transient, and they do not contribute to the microglial pool (11). Given these results, microglia are a cardinal example of a tissue macrophage population derived from embryonic progenitors in the yolk sac and maintained independently of input from hematopoietic stem cells.

Microglia also differ from monocytes by virtue of the factors that regulate their development. CSF-1 and its receptor (CSF-1R) control the differentiation of most macrophage populations in adult mice. During embryogenesis, however, CSF-1R expression is required for yolk sac macrophages and microglial development but not for monocytes (9). Additionally, IL-34 and CSF-1, the established ligands of CSF-1R, act in complementary and partially compensatory fashions toward microglia. In particular, IL-34 deficiency affects microglial cell number in specific regions of the adult brain (12), indicating a selective role for IL-34 in microglial survival and homeostasis in the adult brain. Extending these insights, it was found that mouse microglia derive from primitive c-kit+ erythromyeloid precursors that are detected in the yolk sac as early as E8 (13). Also, microgliogenesis is dependent on Pu.1, and it also requires Irf8, whereas Myb, Id2, Batf3, and Klf4 are not required (13). TGF-β was recently identified as a major differentiation factor for microglia (Fig. 1). The lack of TGF-β affects microglial development beginning at E14.5, but it does not affect microglial progenitors at the E10.5 stage (14). A deeper understanding of the mechanisms that control developmental microglial proliferation and differentiation, as well as maintenance, in the adult brain is important for clarifying microglial responses to brain disorders and how they differ from those of monocyte-derived cells.

As macrophages of the CNS, microglia are the primary immune effector cells in the brain parenchyma. A more comprehensive understanding shows that microglia contribute materially to brain development and homeostasis, because their activities include regulation of cell death, synapse elimination, neurogenesis, and neuronal surveillance in the healthy brain. Microglial cells also promote programmed neuronal cell death during development. A recent study using Nanostring expression profiling and Ingenuity Pathway Analysis revealed that the functions most associated with microglia were related to nervous system development (14). Based on these physiological functions, microglial responses in pathological states will define disease outcomes as much by loss-of-homeostatic function as by gain-of-toxic function or deployment of protective or trophic function. This concept is lost when microglia are termed “resting” or “activated.” In that sense, these categories are no longer useful.

Highly ramified microglia were presumed to be resting and inactive in the healthy brain. In vivo imaging approaches significantly changed our view of microglia by showing that they are found in a state of continuous spontaneous movement in the healthy adult brain (15, 16). Microglia constantly scan their environment, including neurons and astrocytes, with long cellular processes that undergo continuous cycles of extension, withdrawal, and de novo formation (15). This physiological motility may serve, in part, a housekeeping function, enabling microglial cells to effectively patrol the microenvironment and to clear accumulated metabolic products and deteriorated tissue components.

Amoeboid microglia phagocytose apoptotic neurons associated with programmed cell death (PCD) (17). This process is understood to comprise a number of discrete signaling interactions, including the microglial response to neuronal “eat me” signals, microglia priming neurons for PCD, and microglia directly triggering PCD by the release of neurotoxic substances (18, 19). In mammals, one “eat me” signal is phosphatidylserine (PS), which is exposed on the outer leaflet of the plasma membrane of dying or highly stressed cells (20). In addition, apoptotic cells display multiple “eat me” markers, and their combinatorial signaling to phagocytes (including downregulation of “don’t eat me” signals) enhances engulfment. PS binds adhesive “bridging” molecules present in extracellular fluid, such as C3bi, which promotes phagocytosis through its recognition by complement receptor-3 (CD11b) expressed by macrophages. Milk fat globule epidermal growth factor-8 (lactadherin) is a soluble protein that can bind PS and serve as an adaptor to vitronectin receptor (αvβ3/5 integrins) on phagocytes to promote uptake of apoptotic or stressed cells. Calreticulin and annexin A1 colocalize with PS on the surface of apoptotic cells (21, 22). Brain-specific angiogenesis inhibitor 1 is a receptor that directly recognizes PS on apoptotic cells and promotes phagocytosis (23). The externalization of PS on neurons is not synonymous with cell death and is reversible. Under specific circumstances, microglia may phagocytose viable neurons and contribute to pathogenesis (24) (Fig. 1).

In the healthy CNS, microglia remove cellular debris without changing their ramified phenotype. In large CNS injuries causing extensive neuronal death, demyelination, or blood hemorrhage, signals termed damage-associated molecular patterns (DAMPs) are released by damaged neural cells or provided by plasma proteins to which microglia are never exposed in the healthy brain. DAMPs promote microglial morphological transformation and gene expression changes, likely by altering the balance between “on” and “off” signals. “Off” signals are generated constitutively in the healthy brain and help to establish the physiological microglial phenotype. Many of the known “off” signals are neuronally derived, including fractalkine paired with the microglial receptor CX3CR1, CD200 paired with microglial CD200R1, CD22 with microglial CD45; and CD47 with microglial CD172a/SIRPα (25) and TREM2b (1, 26). Additionally, the blood–brain barrier excludes all plasma proteins, so that entry of these components delivers a potent “on” signal to microglia. In pathological states, “on” signals, such as increased extracellular ATP and UTP from damaged neural cells, prevail over “off” signals, resulting in the phenotypic change of microglial cells, including altered morphology, proliferative capacity, and gene expression.

In mammals, including primates, neurogenesis occurs predominantly in the subgranular zone of the dentate gyrus in the hippocampal formation and in the subventricular zone of the lateral ventricle (27). Neurogenesis occurs throughout life in the adult brain, and ramified microglia are an essential component of the neurogenic niche in the subgranular zone of the adult hippocampus. Apoptotic neurons are removed by ramified microglia in the healthy CNS. Microglia direct the migration and differentiation of neural progenitor cells by secreting soluble factors that promote neurogenesis (28). During the first postnatal week of life, Layer V cortical neurons require microglial accumulation along subcerebral and callosal projection axons because microglia-derived insulin-like growth factor 1 is an important factor for neuron survival (29). In adult mice, removal of microglial brain-derived neurotrophic factor (BDNF) resulted in deficits in multiple learning tasks and a significant reduction in motor learning–dependent synapse formation (30). Microglial BDNF increased neuronal tropomysin-related kinase receptor-B phosphorylation, a key mediator of synaptic plasticity, which suggests that microglia have important physiological functions by promoting learning-related synapse formation (30) (Fig. 1).

Signaling by fractalkine (CX3CL1) to its receptor (CX3CR1) is a well-characterized example of a neuron–microglia communication system in the neurogenic niche. CX3CR1 is expressed by all microglia in the brain, and CX3CL1 is constitutively expressed at high levels on healthy neurons. Lack of, or a reduction in, CX3CR1 results in decreased neurogenesis, disruption of hippocampal circuit integrity, and impairments in spatial learning and other behavioral and learning tasks (31, 32). Neuronal loss and enhanced neurodegeneration and inflammation also occur in models of Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) (26). Reintroducing CX3CL1 into the hippocampus of aged animals rescues the decreasing neurogenesis generally observed in aging animals (33). These studies suggest that microglial dysfunction has a significant impact on neuronal function.

There has been extensive investigation of putative roles of microglia in the context of disease, including injury models, cerebral ischemia, and neurodegenerative diseases. Microglia have been attributed an extraordinary ability to respond rapidly and perform a broad range of functions. For example, in the laser-lesion model, microglia near the site of the laser-ablated lesion respond within minutes by polarizing their highly motile processes toward the lesion (16). Microglia in cerebral ischemic lesions dramatically increase synaptic contacts, followed by frequent disappearance of the presynaptic terminal (34). Further analysis showed that microglia play a role in remodeling synapses under physiological conditions, particularly during development. Microglia interact with spines, synaptic terminals, and synaptic clefts in the developing primary mouse visual cortex V1 in vivo (35). Spines often change size upon microglial contact, and the spines that microglia alter are eliminated, suggesting that microglia may be key regulators of structural spine plasticity and elimination of spines. Furthermore, retinal TGF-β secreted by astrocytes regulates neuronal C1q expression, resulting in C3-dependent microglial synaptic elimination in the developing brain (36). Of note, these activities of microglia are regulated by neuronal activity.

It was hypothesized that microglia play an active role in synapse stripping, a process in which microglia selectively remove synapses from injured neurons. However, several studies of nerve injury showed that microglia proliferation following the injury is not an essential process in the remodeling or withdrawal of presynaptic contacts from an injured neuron (37). In murine prion disease, the loss of presynaptic boutons is an initial event preceding degeneration of the cell body. Also, in ALS, synapses at the neuromuscular junction degenerate prior to the cell body. It is suggested that the presynaptic degeneration occurs independent of synaptic activity and synaptic vesicle recycling (38, 39) and that the synaptic loss is a neuron-autonomous event facilitated without direct involvement of microglial cells (40). Understanding mechanisms of synapse degeneration will be crucial, because cognitive decline is strongly correlated with loss of presynaptic terminals.

The CNS is immune privileged, secluded from circulation by the blood–brain barrier, and is equipped with its own myeloid cell population, the microglial cells. Based on the classical perspective of immune–brain interactions, infiltrating macrophages were traditionally viewed as pathogenic by definition. However, over the past two decades, research has revealed a pivotal role for monocyte-derived macrophages in CNS repair and has opened up new avenues for understanding and treating CNS pathologies. In this review, we discuss the diversity of monocyte-derived macrophages, the induction and resolution of inflammation, as well as monocyte involvement in neural tissue regeneration and renewal, matrix remodeling, debris clearance, and angiogenesis.

Because of the diversity of monocyte-derived macrophages, their roles in the CNS are controversial. Monocyte-derived macrophages have multiple subpopulations according to their locations, surface markers, and phenotypes. Distinct types of macrophages are found in different locations in the CNS, including perivascular cells, meningeal macrophages, and blood-borne monocytes, and they differ in their morphology and functions (41, 42). Monocytes are blood mononuclear cells that express CD11b, CD11c, CD14, and (variably) CD16 in humans and CD11b and CD45 in mice. In the CNS, perivascular macrophages, meningeal macrophages, and choroid plexus macrophages, which control local immune surveillance, are CX3CR1+ CD11b+ CD45high. Although inflammatory monocytes (Ly6Chigh CCR2+ CX3CR1low) are highly motile and are rapidly recruited to inflamed tissues, a nonoverlapping population of blood monocytes (Ly6Clow CCR2low/− CX3CR1high) is proposed to be important for patrolling along blood vessels (and are termed “patrolling monocytes”) (43). In the steady-state, Ly6Clow monocytes originate from Ly6Chigh blood monocytes (44). The Ly6Chigh CCR2+ monocytes are able to produce inflammatory molecules, such as TNF-α and inducible NO synthase (iNOS) (45). Disease-specific mobilization and recruitment of CD11b+ Ly6Chi CCR2+ monocytes into the inflamed CNS was recently observed in a number of studies (46, 47).

Macrophages have remarkable plasticity that allows them to efficiently respond to environmental signals and change their phenotype, and their physiology can be markedly altered by both innate and adaptive immune responses. Two useful macrophage phenotypes are termed M1 (IFN-γ–stimulated inflammatory macrophages) and M2 (IL-4– or IL-13–stimulated alternatively activated cells). The reckless application of these limited polarized state terminologies to other circumstances threatens to vitiate their meaning. It has been universally observed that the myeloid compartment has an extremely broad transcriptional repertoire depending on the different environmental signals in chronic inflammation, chronic infection, or cancer. A study of human macrophages with transcriptome–based network analysis delineated nine distinct macrophage-activation programs (48) expressed in response to a suite of stimuli in vitro. When adding stimuli, such as free fatty acids, high-density lipoprotein, or stimuli associated with chronic inflammation, a spectrum of macrophage-activation signatures quickly overwhelmed the bipolar axis demonstrated by cells treated with type II IFN or IL-4/IL-13 (Fig. 1). This study also identified transcription factors associated with particular phenotypes. Further understanding of the transcriptional regulation of macrophages would help to selectively target specific subsets therapeutically.

Monocytes are heterogeneous under neurodegenerative conditions in the CNS. Anti-inflammatory treatment with FK506 or minocycline, a synthetic tetracycline derivative, decreases phagocytic activation and lesion size after injury and confers variable degrees of neuroprotection in spinal cord injury, traumatic brain injury, and stroke (4951). Early depletion of presumed peripheral macrophages using clodronate diminishes secondary tissue damage and was shown to have some beneficial effect (52). However, monocyte-derived macrophages also show immune-resolving characteristics and express anti-inflammatory cytokines. These cells contribute to motor function recovery following spinal cord injury (53) and promote survival of neurons and cell renewal in the injured retina (54). Moreover, they restrict accumulation of other inflammatory leukocytes, including neutrophils and resident microglia, mediate debris clearance by phagocytosis, and regulate the extracellular matrix and glial scarring surrounding the damaged area (55).

In the multiple sclerosis model experimental autoimmune encephalitis, CCR2+ Ly6Chigh monocytes are rapidly recruited to the inflamed CNS and play a crucial role in the effector phase of the disease (47). MHC class II–expressing macrophages are responsible for reactivation of pathogenic T cells at the CNS borders, the subarachnoid spaces of the meninges, and the perivascular spaces of the blood–brain barrier (56). Using double Cx3cr1GFP/CCR2RFP-transgenic mice, it was shown that both Ly6chigh/CX3CR1low and Ly6clow/CX3CR1high monocyte-derived macrophages are present at the demyelination sites in experimental autoimmune encephalitis, whereas only the former are recruited in a CCR2-dependent manner and are believed to contribute to the activation of resident microglia (57).

One remaining question is: How do microglia and monocytes communicate with or regulate each other? Even when a stimulus is strong, but short-lived, microglia can potentially cope with the danger signal, performing clearance of neurotoxic factors, supporting regeneration, and secreting neurotrophic factors supportive of remyelination. However, when the stimulus is intense or chronic, microglia can no longer handle the damage. These cells become neurotoxic and release reactive oxygen species, NO, proteases, and inflammatory cytokines, all of which endanger neuronal activity (58). These activation stimuli result in signals for recruitment of monocytes to the damage site, which restrict inflammation, restore homeostasis, and support healing and renewal. In a mouse model of ALS, microglia expressed increased CCL2 and other chemotaxis-associated molecules, which led to the recruitment of monocytes to the CNS (59). Impaired CX3CR1 signaling alters monocyte recruitment and its subsets after spinal cord injury (60). As a result, a CD11b+ Ly6Clow iNOS+ MHCII+ CD11c population dominates the injury site of wild-type mice, whereas CD11b CCR2+ Ly6Chigh MHCII CD11c+ cells predominate in spinal cord of CX3CR1GFP/GFP-knockout mice. Mechanisms controlling diversity in CNS macrophages are not well defined.

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive loss of memory and other cognitive functions. Pathological characteristics of the AD brain are amyloid-β (Aβ) accumulation, neurofibrillary tangles, synaptic loss, and neurodegeneration. Microglia accumulate around senile plaques in patients with AD and in animal models of AD. However, their role in the pathogenesis of AD remains to be elucidated. The response of microglia to Aβ peptides has been studied intensively because it was proposed that phagocytosis of these peptides by microglia could ameliorate the pathogenic cascade that occurs in the brains of AD patients. Microglia secrete proteolytic enzymes that degrade Aβ (61) and express receptors that promote the clearance and phagocytosis of Aβ (62, 63). However, microglia are also activated by Aβ and, once activated, release inflammatory mediators that could promote AD pathology (64). It was demonstrated with live imaging by two-photon microscopy that Cx3cr1 knockout prevents neuronal loss in a triple-transgenic mouse model of AD (65), although the extent of neuronal loss in this model is modest. Lack of CX3CR1 in microglia disrupts CX3CL1–CX3CR1 interactions, dysregulates microglial activity induced by neuronal stress, and results in enhanced release of soluble factors, including IL-1, from activated microglia. Other studies showed that Cx3cr1 deficiency results in a gene dose-dependent reduction in Aβ deposition (66). Moreover, Cx3cr1−/− microglia had an enhanced ability to phagocytose Aβ. Elucidating the regulatory effect of CX3CR1 on microglial functions in specific pathological environments will contribute to developing novel neurotherapeutics.

The role of monocytes in AD pathology was reported to be beneficial. Studies using various conditional cell-depletion strategies in a mouse model of AD showed that blood-derived macrophages can prevent the formation of, or eliminate, Aβ deposits (67, 68). Especially, the recruited blood-derived macrophages contribute to efficient amyloid elimination while arresting the local production of proinflammatory factors, including TNF (69). Stimulating perivascular macrophage turnover reduced cerebral amyloid angiopathy load, independently of clearance by microglia (70). Monocyte-derived perivascular macrophages restrict vascular amyloid (dependent on CCR2) and promote Aβ transit to the vessel lumen. CX3CR1+ monocytes interact with Aβ+ vessel walls and take up Aβ (dependent on CX3CR1). Additionally, an important role for Ly6C monocytes in the clearance of vascular Aβ was reported in AD-transgenic mice (71). Using intravital two-photon microscopy, it was demonstrated that patrolling Ly6Clow monocytes monitor veins containing small Aβ aggregates but not Aβ+ arteries or Aβ-free blood vessels. These monocytes crawl inside the lumen of blood vessels, independently of the direction of blood flow, scavenging Aβ. Moreover, the crawling monocytes carrying Aβ in veins recirculate back into the bloodstream. Depletion of Ly6C monocytes increased amyloid load in the cortex and hippocampus. These data suggest the possibility of Ly6C monocytes as a therapeutic target in AD.

Recent studies revealed multiple genetic risk factors for susceptibility to AD, including polymorphic variants of the myeloid cell molecules CD33 and TREM2. The expression of CD33 in microglial cells in AD brain is increased, and the numbers of CD33+ cells correlated with insoluble Aβ levels (72). CD33 expression on monocytes is also observed, and these cells have a reduced ability to phagocytose Aβ (73). In vitro, TREM2 on microglial cells stimulates phagocytosis on one hand and suppresses cytokine production and inflammation on the other (74, 75). In particular, TREM2 knockdown impaired phagocytosis of apoptotic neurons and increased TNF-α and iNOS expression (75). Therefore, these molecules may have the ability to suppress inflammatory responses during the period of debris clearance after CNS injury.

PD, another neurodegenerative disorder, is characterized by the loss of dopaminergic neurons and dystrophic neurites in the substantia nigra. Mice deficient in CX3CR1 show increased microglial activation and enhanced dopaminergic cell loss in the substantia nigra after LPS administration (26). It also was shown that CD200-CD200R blocking exacerbates neurodegeneration in a rat model (76). Moreover, CX3CR1GFP/+ microglia have cell-to-cell contact with neurons, and some microglia penetrate neuronal somata (77). These results suggest possible microglial involvement in the pathogenesis of PD. Infiltration of monocytes has not been reported, and the role of monocytes in PD is unknown. DAP12 knock-in mice, in which macrophages are defective in their number and functions, exhibited less neuronal loss in a murine model of PD compared with naive mice. Further analyses to resolve the different role between microglia and monocytes in PD are required.

ALS is another neurodegenerative disease affecting the motor system. There is increasing evidence that microglia are key components in ALS motor neuron degeneration. Mutation in superoxide dismutase 1 (mSOD1) is the most prominent cause of familial ALS. mSOD1 motor neurons cocultured with wild-type microglia did not exhibit cell death, whereas mSOD1 microglia induced wild-type motor neuron degeneration (78). Similarly, deletion of mSOD37R specifically from CD11b+ myeloid cells extended the survival of mice significantly, particularly during the late phase of disease (79). Moreover, microglia express CCL2 and other chemotaxis-associated molecules, which lead to the recruitment of CCR2+ Ly6Chigh monocytes to the spinal cord. This monocyte recruitment correlates with neuronal loss (59). Of note, transplantation of mSOD1G93A microglia into PU.1−/− mice did not induce motor neuron degeneration, indicating that mSOD1 in microglia alone is not sufficient to initiate disease (80).

We have briefly discussed differences between microglia and monocytes in terms of their origin and roles in the CNS. Although triggers of microglia and monocyte reactions in diseases have been extensively studied, these phenomena are complex and differ from disease to disease. Further efforts to reveal how they are controlled will be required.

We thank Lisa Spangler and Chris Nelson for helpful suggestions. We apologize to those whose work could not be discussed because of space constraints.

This work was supported by the National Institutes of Health, the National Multiple Sclerosis Society, the Alzheimer’s Association, the Guthy Jackson Charitable Foundation, the Department of Defense, and the Williams Family Fund.

Abbreviations used in this article:

amyloid-β

AD

Alzheimer’s disease

ALS

amyotrophic lateral sclerosis

BDNF

brain-derived neurotrophic factor

DAMP

damage-associated molecular pattern

E

embryonic day

iNOS

inducible NO synthase

mSOD1

mutation in superoxide dismutase 1

PCD

programmed cell death

PD

Parkinson’s disease

PS

phosphatidylserine.

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The authors have no financial conflicts of interest.