A JOURNAL OF NEUROLOGY
Debris clearance by microglia: an essential link
between degeneration and regeneration
H. Neumann,1M. R. Kotter2,3and R. J. M. Franklin4
1 Neural Regeneration, Institute of Reconstructive Neurobiology, University Bonn, Bonn, Germany
2 Department of Neurosurgery, Medical University Vienna, Vienna, Austria
3 Department of Neurosurgery, University of Go ¨ttingen, Go ¨ttingen, Germany
4 Department of Veterinary Medicine and Cambridge Centre for Brain Repair, University of Cambridge, Cambridge, UK
Correspondence to: Harald Neumann,
Institute of Reconstructive Neurobiology,
University Bonn and Hertie-Foundation,
Sigmund-Freud-Str. 25, 53127 Bonn, Germany
Microglia are cells of myeloid origin that populate the CNS during early development and form the brain’s innate immune
cell type. They perform homoeostatic activity in the normal CNS, a function associated with high motility of their ramified
processes and their constant phagocytic clearance of cell debris. This debris clearance role is amplified in CNS injury, where
there is frank loss of tissue and recruitment of microglia to the injured area. Recent evidence suggests that this phagocytic
clearance following injury is more than simply tidying up, but instead plays a fundamental role in facilitating the reorganization
of neuronal circuits and triggering repair. Insufficient clearance by microglia, prevalent in several neurodegenerative diseases
and declining with ageing, is associated with an inadequate regenerative response. Thus, understanding the mechanism and
functional significance of microglial-mediated clearance of tissue debris following injury may open up exciting new therapeutic
Keywords: neuroinflammation; microglia; neurodegeneration; regeneration; phagocytosis; multiple sclerosis, Alzheimer disease
Abbreviations: Ab=amyloid-b; BDNF=brain derived neurotrophic factor; CR3=complement receptor type 3; EAE=experimental
autoimmune encephalomyelitis; IGF-1=insulin-like growth factor-1; IL-4=interleukin-4; TLRs=toll like receptors; TNF-?=tumour
necrosis factor-?; TREM-2=triggering receptor expressed on myeloid cells-2
Over several decades the question of whether microglia and brain
macrophages play harmful or beneficial roles in CNS injury and
disease has been widely debated and reviewed (Streit, 2005,
2006; Block et al., 2007; Hanisch and Kettenmann, 2007). In
our view it is clear that they can fulfil both roles and we do not
intend to argue for one position against the other. Instead, we
start with the premise that microglia perform many beneficial roles
in diseases and review how recent advances in our understanding
of microglial biology relate to these, highlighting how phagocytic
removal of tissue debris has an important function in creating a
pro-regenerative environment within the CNS. Microglia engaged
in phagocytosis generally assume a macrophage phenotype, which
is indistinguishable from the macrophage phenotype assumed by
monocyte-derived cells. Recent evidence demonstrates that transi-
tion of monocyte-derived cells into microglia is a very rare event
that only occurs under very defined host conditions (Mildner
et al., 2007). In general microgliosis arises as a result of a prolif-
erative response of resident microglia, present within the CNS due
to invasion by myeloid precursors during development (Ajami
et al., 2007; Ransohoff, 2007). Therefore, in this article the term
doi:10.1093/brain/awn109Brain 2009: 132; 288–295 |
Received March 5, 2008. Revised May 8, 2008. Accepted May 9, 2008. Advance Access publication June 20, 2008
? 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/
2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
macrophage will be used to infer a cell of predominantly CNS
origin, if not explicitly defined as blood- or monocyte-derived
Under pathological conditions such as infectious diseases, stroke
or neurodegenerative processes, microglia become activated,
migrate to and within the lesion site, release a wide range
of soluble factors that include cytotoxins, neurotrophins and
immunomodulary factors and clear cellular debris by phagocytosis.
Until recently it was thought that, in contrast to their frenzied
activity in pathology, microglial cells under normal conditions
are quiescent and non-motile cells. However, in vivo imaging
on living mice has revealed that their highly ramified processes
are remarkably motile, continuously and randomly undergoing
cycles of filopodia-like protrusion formation, extension and with-
drawal of bulbous tips (Davalos et al., 2005; Nimmerjahn et al.,
2005). This high motility of the processes enables microglia to
effectively monitor the status of the local surroundings and
possibly to endocytose small cellular debris or budded vesicular
structures, including that from apoptotic cells, from the micro-
environment. Thus microglia might behave like monocyte-derived
macrophages, whose filopodia can act as phagocytic or endocytic
tentacles, efficiently pulling engulfed vesicular material towards
the cell body (Kress et al., 2007). In addition to the high motility
of their processes under normal conditions, they polarize and con-
verge their processes at sites of brain injury attracted by extra-
cellular ATP and mediated via microglial purinoreceptors (Davalos
et al., 2005; Haynes et al., 2006). Recently, it was shown by
in vivo two-photon microscopy that not only the processes, but
also the cell bodies of microglial cells are activated and recruited
to newly formed amyloid-b (Ab) plaques within 1–2 days in an
animal model of Alzheimer’s disease (Meyer-Luehmann et al.,
An important function of microglial cells responding and mig-
rating towards the chemokine ligand of CX3CR1 appears to be
the support of endangered neurons since deficiency in the chemo-
kine receptor CX3CR1 resulted in increased neuronal death in
animal models of amyotrophic lateral sclerosis and Parkinson’s
disease (Cardona et al., 2006). The precise mechanisms by
which CX3CR1-positive microglia might assist compromised neu-
rons have yet to be determined, although it seems likely that it
will relate in part to the release of neuroprotective and trophic
Microglial production of
trophic factors and protective
Microglial cells are able to produce and release a plethora of
soluble mediators ranging from cytotoxic mediators to trophic
factors, which can exert deleterious as well as beneficial effects
on the surrounding tissue. Important insights into this dual nature
are derived from in vitro experiments using organotypic hippo-
campal slice cultures, where it has been shown that microglia
become neurotoxic following treatment with lipopolysaccharides
(LPS) but become neuroprotective when pre-activated with
interleukin-4 (IL-4) (Butovsky et al., 2006). The protective effect
of IL-4 conditioned microglia is associated with a downregulation
of tumour necrosis factor-? (TNF-?) and an upregulation of
has neuroprotective effects but also exerts survival and pro-
regenerative activities on oligodendrocyte-lineage cells, preventing
acute glutamate-mediated toxicity and promoting oligodendrocyte
differentiation from precursor cells in vitro (Ness and Wood, 2002;
Hsieh et al., 2004; Butovsky et al., 2006). Brain derived neuro-
trophic factor (BDNF), having both protective and growth pro-
moting effects on neurons, was suggested to be produced by
microglial cells and to stimulate axonal sprouting towards a
wound edge (Batchelor et al., 2002). Recent data also indicate
that microglial-derived BDNF is implicated in neuropathic pain by
causing a shift in the neuronal anion gradient of spinal lamina I
neurons, thus contributing to tactile allodynia (Coull et al., 2005).
However, it is unclear whether microglia in vivo produce and
release sufficient amount of BDNF for these effects on neurons.
Under certain conditions microglial cells are able to produce
anti-inflammatory cytokines such as IL-10 and transforming
growth factor-b (TGF-b), which have neuroprotective effects
in experimental animal models of traumatic injury and stroke
(Streit, 2005; Hanisch and Kettenmann, 2007). Often, a clear dis-
tinction between cytokines that are either harmful or beneficial
cannot be made since the primarily cytotoxic pro-inflammatory
cytokines IL-1b and TNF-? released from activated microglia can
directly or indirectly evoke a neuroprotective or pro-myelin regen-
erative response. For example, TNF-? has been shown to protect
neurons against Ab mediated toxicity (Barger, 1995) under patho-
logical conditions and the absence of glial derived TNF-? revealed
a role in homoeostatic synaptic scaling under physiological condi-
tions (Stellwagen and Malenka, 2006).
The release of cytokines, chemokines and other soluble media-
tors is the first step for successful repair and contributes to
the creation of an environment conducive for regeneration. The
factors secreted attract phagocytic and repair-promoting effector
and precursor cells, which are able to replace damaged tissue.
This process is especially evident during remyelination, the regen-
erative event in which new myelin sheaths are restored to demye-
linated axons and that can occur with impressive efficiency in
experimental models and clinical disease (Ludwin, 1978, 1980;
Woodruff and Franklin, 1999; Sim et al., 2002; Patrikios et al.,
2006; Patani et al., 2007). Studies of remyelination in animals
lacking pro-inflammatory cytokines such as TNF-? (Arnett et al.,
2001, 2003) and IL-1b (Mason et al., 2001) have suggested
that inflammatory cytokines and, as will be discussed later, the
inflammatory response to demyelination are required to trigger
efficient remyelination. The remyelination-enhancing effects of
IL-1b and TNF-? could be due to direct effects or indirectly
mediated via the induction of IGF-1 (Arnett et al., 2001, 2003),
although IGF-I is likely to be a redundant component of environ-
mental factors governing remyelination (O’Leary et al., 2002).
In addition to trophic and pro-regenerative effects of secretory
Debris clearance by microgliaBrain 2009: 132; 288–295 |
factors directly or indirectly derived from microglia, the phagocytic
clearance of debris is also instrumental for repair as discussed in
the following sections.
There are two distinct functional types of phagocytic receptors.
First, receptors recognizing microbes such as toll like receptors
(TLRs) which support removal of pathogens and simultaneously
(Ravichandran, 2003), and second, receptors recognizing apopto-
tic cellular material such as receptors that recognize phosphatidyl-
serine (PS) and which are important for ingesting apoptotic cell
corpses and stimulate an anti-inflammatory response in phago-
cytes (Ravichandran, 2003). This silent phagocytosis that takes
place without inducing inflammation is one of the major beneficial
functions of phagocytes (Fig. 1).
The specificity of these phagocytic receptors and their respec-
tive ligands are often unknown but are gradually beginning
to emerge. For example, T-cell immunoglobulin- and mucin-
domain-containing molecule-4 (Tim4) has recently been shown
to recognize phosphatidylserine residues (Miyanishi et al., 2007).
In addition, a number of microglia-specific phagocytic receptors
have been observed recently, including microglial metabotropic
P2Y6 receptor that recognizes the nucleotide UDP released from
injured neurons and stimulates microglial phagocytosis (Koizumi
et al., 2007). Furthermore, triggering receptor expressed on mye-
loid cells-2 (TREM2)-mediated signalling in microglia has been
shown in vitro to facilitate debris clearance in the absence of
inflammation (Takahashi et al., 2005). The paramount importance
of these receptors has recently become clear as patients with a
loss of function mutation of either TREM2 or DAP12 develop
an inflammatory neurodegenerative disease leading to death
at the fourth or fifth decade of life. Thus, even though the
ligand of TREM2 is unknown, microglial TREM2/DAP12-mediated
phagocytosis appears to be an essential function for CNS tissue
homoeostasis (Neumann and Takahashi, 2007).
Microglial phagocytosis during
restructuring of neuronal
Selective synapse elimination and axon pruning are vital late-stage
refinements in the formation of functional neural circuits. In the
brain of the adult fruitfly Drosophila a program involving glia acts
to achieve pruning of the axonal connection of the mushroom
body ? neuron (Broadie, 2004). Phagocytic glial cells actively
invade the mushroom body lobes and engulf axonal varicosities
prior to the axonal degeneration and accumulate acidic degrada-
tive organelles at the time of axonal pruning (Awasaki and Ito,
2004; Awasaki et al., 2006). Insect glial cells appear to be active
phagocytes, which engulf the axons and synapses by an extrinsic
mechanism (Awasaki and Ito, 2004; Awasaki et al., 2006). While
microglial cells in mammals are the principal phagocytes in the
CNS, Schwann cells of the peripheral nervous system (PNS) can
assist blood-derived macrophages in removing myelin debris and
have been recognized as playing a key role in synapse removal
during development of the PNS (Bishop et al., 2004). During
development of the murine CNS, apoptotic neurons and their
connections, which have been established in excess, are actively
and rapidly removed by microglia (Frade and Barde, 1998; Marin-
Teva et al., 2004). At the initial but still reversible stages of pro-
grammed cell death of developing Purkinje neurons, caspase-3-
mediated activation of Ca-independent phospholipase A2 results
Fig. 1 Microglial phagocytic receptors. Phagocytosis is
associated with inflammation during uptake of microbes,
while phagocytosis of apoptotic cells is executed without
inflammation. Recognition of microbes induces a microglial
phagocytic response, which is associated with release of
pro-inflammatory mediators such as TNF and NO. Particularly,
TLRs recognize microbial patterns leading to pro-inflammatory
activity release in microglial cells. Furthermore, Fc-receptor
(FcR) engagement antibodies binding induces pro-inflammatory
activity dependent of the Fc-receptor subtyp and antibody
isotype. Recognition and phagocytosis of apoptotic cells
induces an anti-inflammatory cytokine profile in microglia.
Phosphatidylserine receptors (PRs) recognizing
phosphatidylserine residues in apoptotic membranes stimulated
microglial production and release of TGF-b and IL-10.
Triggering receptor expressed on myeloid cells-2 (TREM2)
induces anti-inflammatory activity of microglia. Purine receptors
(PRs) such as P2Y6 are recognizing UDP. Phagocytic receptors:
PRs=purine receptors; PSRs=phosphatidylserine receptors;
CRs=complement receptors; TLRs=toll like receptors;
FcR=Fc-receptors; SRs=scavenger receptors;
TREM2=triggering receptor expressed on myeloid cells-2.
Soluble mediators: TNF=tumour necrosis factor-?; IL-1=
interleukin-1b; NO=nitric oxide; TGF-b=transforming growth
Brain 2009: 132; 288–295 H. Neumann et al.
in the production of pysophosphatidylcholine and exposure of
phosphatidylserine on the cell membrane, leading to active cell
death and removal by microglial cells (Marin-Teva et al., 2004).
Recent data indicate that microglia via its complement receptor
C3 might be involved in synapse removal of unwanted synapses
that have been tagged by complement for elimination during
development (Stevens et al., 2007). Complement C1q and
C3, both components of the classical complement cascade, are
expressed by distinct synapses throughout the postnatal CNS.
Mice deficient in C1q or C3 exhibited large sustained defects
in CNS synapse elimination, as shown by the failure of anatomical
refinement of retinogeniculate connections and the retention of
excess retinal innervation by lateral geniculate neurons. Our
knowledge of the removal mechanism of synapses and axons
during reorganization of the normal and injured adult mammalian
CNS is still incomplete, nevertheless it is becoming increasingly
clear that microglia play a central role.
Microglial phagocytosis in
acute CNS injury
In acute injury, microglia has been shown to react within a few
hours with a migratory response towards the lesion. For example,
in an in vitro model of entorhinal cortex injury microglia migrated
towards the zone of axonal degeneration where loss of the dener-
vated dendrites of interneurons occurred (Rappert et al., 2004).
This migration is functionally significant since in chemokine recep-
tor CXCR3 deficient mice, where microglia do not migrate, no
loss of dendrites was observed (Rappert et al., 2004). Thus, dener-
vated neuronal dendrites are not retracted autonomously, but
require a trigger signal or active removal by microglia. Similarly,
in response to an experimental axonal lesion to facial nerve moto-
neurons in rats, a glial cell mediated removal or ‘stripping’ of
synapses from the perikaryon and dendrites of affected cells
has been reported (Streit, 2005). It was recently suggested that
microglia and major histocompatibility complex (MHC) class I
related receptors take up a main role in the process of synapse
removal after motoneuron injury (Cullheim and Thams, 2007).
In most cases of acute injury deposition of tissue debris is
observed due to cell death. In general tissue debris does not
linger for long periods after tissue damage due to efficient removal
by macrophages. However, in the CNS the myelin debris asso-
ciated with Wallerian degeneration can persist for very long time
periods (Miklossy and Van der Loos, 1991; Vargas and Barres,
2007). In the CNS microglia are the first cell type engaged in
phagocytosis. However, their phagocytic capacity as compared
to blood-borne macrophages might be limited (Mosley and
Cuzner, 1996; Popovich et al., 1999). In the second instance,
blood-borne macrophages assist and could significantly contribute
to the removal of debris (Amat et al., 1996; Stoll and Jander,
1999). The capacity of macrophages to phagocytose myelin
can be altered by environmental mediators. After treatment with
TNF-? a massive reduction of the amount of myelin ingested by
macrophages via their complement receptor type 3 (CR3) occurred
in vitro (Bruck et al., 1992). Immunofluorescence analysis
indicated that TNF-? caused a reduction of CR3. Similarly,
in vivo experiments have demonstrated that pre-activation of
macrophages transplanted into transected optic nerve has pro-
found effects on the rate of myelin clearance (Lazarov-Spiegler
et al., 1998). Myelin contains several growth inhibitory molecules
such as Nogo A, which exhibit inhibitory effects on axonal re-
growth (Schwab, 2004). Thus, the rapid removal of myelin-asso-
ciated inhibitors is important for establishing an environment ben-
eficial for axon regeneration. A number of observations suggest
that insufficient myelin clearance in the CNS after acute injury may
contribute to the failure of axonal regeneration, while efficient
myelin clearance in the PNS during Wallerian degeneration by
Schwann cells and invading and resident macrophages facilitates
axonal regeneration (David and Lacroix, 2003; Vargas and
Barres, 2007). In support of this notion, it was observed that
the transected optic nerve of amphibians exhibits a rapid phago-
cytic response, which leads to an effective clearance of myelin
debris and finally, successful axonal regeneration (Battisti et al.,
1995; Perry et al., 1995).
Recent evidence indicates that the presence of myelin molecules
not only inhibits axonal outgrowth but also affects the differentia-
tion of oligodendrocyte precursor cells into mature oligodendro-
cytes during remyelination (Kotter et al., 2005). Thus, the myelin
debris generated during demyelination needs to be rapidly
removed by phagocytic cells, for remyelination to proceed effi-
ciently. This is reflected in the strong correlation between the
efficiency of remyelination and the effectiveness of myelin debris
removal, both occurring in young animals more effectively than in
older adult animals or young animals in which additional myelin
was experimentally added (Shields et al., 1999; Kotter et al.,
2005, 2006; Dubois-Dalcq et al., 2005).
Microglial phagocytosis in
Phagocytically active macrophages, identified by staining against
myelin degradation products or lysosomal lipids, have been exten-
sively described in multiple sclerosis lesions (Li et al., 1993; Bruck
et al., 1995). Most of these myelin-laden macrophages are loca-
lized in the perivascular areas in active inflammatory lesions.
Phagocytic cells have also been analysed in experimental auto-
immune encephalomyelitis (EAE), an animal model of multiple
sclerosis. During the first attack of acute and chronic relapsing
EAE, immunostaining with an antibody against lysosomal mem-
branes of phagocytes demonstrated at the ultrastructural level
that these phagocytes were seen to contain degraded myelin
products in lysosomes (Bauer et al., 1994). However, the func-
tional role of phagocytosis in EAE is unclear. Recently, a beneficial
role of the microglial phagocytic TREM2 receptors has also been
demonstrated in EAE. Antibody-mediated blockade of TREM2
during the effector phase of EAE results in disease exacerbation
with more diffuse CNS inflammatory infiltrates and demyelination
in the brain parenchyma (Piccio et al., 2007). In another study,
intravenous transplantation of myeloid precursor cells genetically
engineered to over-express TREM2at the clinical peak of EAE
Debris clearance by microgliaBrain 2009: 132; 288–295 |
improved myelin removal in the lesioned spinal cord, created an
anti-inflammatory cytokine profile in the lesions and facilitated
recovery (Takahashi et al., 2007). Thus, debris clearance by resi-
dent endogenous microglia appears to be insufficient and it is
possible to promote recovery in EAE by the transplantation of
phagocytic TREM2 positive cells that contribute to the clearance
Microglial phagocytosis in
In Alzheimer disease microglia can be beneficial by phagocytosing
Ab or harmful by secretion of neurotoxins. Recently it was shown
in an animal model of Alzheimer disease plaque formation that
microglia accumulation is associated with rapid appearance and
local toxicity of Ab plaques (Meyer-Luehmann et al., 2008)
(Fig. 2). Using in vivo multiphoton microscopy plaques were
revealed to form over 24h followed within 1–2 days by microglial
activation and recruitment to the plaque, and finally the appear-
ance of dysmorphic neurites over the next days to weeks. In an
animal model oftauopathy,exhibitingcertain aspectsof
neurofibrillary tangle formation of Alzheimer disease, early micro-
glia activation was associated with loss of synapses preceding
tangle formation (Yoshiyama et al., 2007). In APP/PS1 and
APP23 transgenic mice, bone marrow-derived myeloid cells were
recruited to senile plaques and differentiated into microglial-like
cells after irradiation and bone marrow transplantation (Malm
et al., 2005; Stalder et al., 2005). Invading bone marrow-derived
cells gradually obtained morphologies and lineage markers very
similar to resident microglia. However, CNS invasion of bone
marrow derived cells might be induced by irradiation performed
for the transplantation of bone marrow cells, and not a conse-
quence of the disease process (Mildner et al., 2007). Furthermore,
it is unclear whether bone marrow-derived cells develop a real
microglia phenotype, since resident microglia underwent a distinct
developmental program coming from the yolk sac and invaded the
CNS during early stages of development. Recently, it was shown
that the chemokine receptor CCR2 expressed on microglia, invad-
ing blood-derived macrophages and circulating monocytes is
required for accumulation of these CD11b+ cells in the CNS in a
transgenic mouse model of Alzheimer disease (El Khoury et al.,
2007). Diseased mice deficient in CCR2 demonstrated increased
perivascular Ab deposits and died prematurely possibly due to
amyloid angiopathy, indicating that CCR2 function on circulating
monocytes or microglia is required for prevention or clearance of
perivascular Ab deposits (El Khoury et al., 2007). Thus, there is
certain evidence that either local microglia or invading blood-
derived macrophages restrict Ab deposits in an animal model of
Microglial phagocytosis in
Ageing is associated with senescence of microglia and impaired
microglial clearance functions. In particular, data indicate that
microglia in aged rodent and human brains show a replicative
senescence with a reduced self-renewal capacity (Streit, 2006).
Microglia in aged animals were characterized by the presence of
lipofuscin granules, decreased processes complexity, altered gran-
ularity and increased mRNA expression of pro-inflammatory cyto-
kines such as TNF-? and IL-1b (Sierra et al., 2007). Furthermore,
older rats compared to young rats showed delayed recruitment of
phagocytic cells and less clearance of myelin after a toxin-induced
demyelination lesion (Zhao et al., 2006), which correlates with the
slower remyelination in older animals (Sim et al., 2002). Thus,
microglia dysfunction occurring as a result of ageing might
contribute to the exacerbation of chronic neurodegenerative dis-
eases and Ab plaque load in Alzheimer disease and a reduced
repair capacity in aged individuals (Fig. 3).
The removal of non-functional or degenerated tissue is an essen-
tial role of microglia. This response is most strikingly seen follow-
ing injury in adulthood and can be viewed as an exaggerated
version of a normal physiological task performed by microglia to
Fig. 2 Detrimental effects of myelin debris and extracellular
aggregates (A) Inhibitory activity of myelin debris in multiple
sclerosis. Immune mediated demyelination and oligodendrocyte
injury liberates myelin. Myelin debris inhibits axonal re-growth
and regeneration. Furthermore, myelin debris inhibits oligo-
dendrocyte precursor cell differentiation. (B) Neurotoxic activity
of Ab plaques in Alzheimer disease. Extracellular Ab directly
damages synapses and stimulates microglial to release neuro-
toxic mediators such as TNF-? and nitric oxide (NO). Microglial
cytotoxic mediators induces synaptic and axonal injury.
Brain 2009: 132; 288–295 H. Neumann et al.
remove superfluous cells undergoing apoptosis in development
and adulthood. If phagocytosis is compromised as it is evident
in loss-of-function mutations of either TREM2 or DAP12, this
results in a chronic degenerative CNS disease. In the context of
a homoeostatic role for microglial phagocytosis, the clearance
function fits comfortably with a pro-regenerative contribution to
the complex events occurring in the damaged CNS. At present
this is most clearly evident in the inefficient remyelination asso-
ciated with inhibition of precursor differentiation and in impaired
axon regeneration in the presence by uncleared myelin debris.
Similarly, limited clearance of affected tissue or dysfunction of
microglia are features of several neurodegenerative diseases and
are exacerbated with ageing. These relatively diverse lines of evi-
dence point to the generic importance of the microglia-mediated
phagocytic removal of debris in creating environments most con-
ducive to intrinsic regenerative processes. Allowing these to occur
will require a deeper understanding of the mechanisms and func-
tional significance of microglia and macrophage-mediated clear-
ance of tissue debris following injury from which new CNS
regenerative medicines may emerge.
The group of H.N. is supported by the Hertie Foundation, the
Rose Foundation, the Deutsche Forschungsgemeinschaft, the
BMBF and the European Union (LSHM-CT-2005-018637). The
group of R.J.M.F is mainly supported by The UK MS Society,
The National MS Society, Research into Ageing and The Wellcome
Trust. M.R.K’s group receives funding from Wings for Life and the
Medical University Vienna.
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Fig. 3 Beneficial microglia function. Microglial beneficial
function is mediated via several effector mechanisms. Firstly,
microglia and invading macrophages clear myelin debris or
extracellular aggregates. Secondly, microglia initiate the
repair process by stimulating neighbouring astrocytes to
produce trophic support factors and by recruiting stem and
precursor cells. Thirdly, microglial cells produce a variety of
neurotrophins, growth factors and anti-inflammatory cytokines
stimulating sprouting of axons and myelin repair. Soluble
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NT3=neurotrophin-3; IGF-1=insulin-like growth factor-1;
IL-10=interleukin-10; IL-1=interleukin-1; TNF=tumour
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