Immunology and Cell Biology (2010) 88, 781–786
& 2010 Australasian Society for Immunology Inc. All rights reserved 0818-9641/10 $32.00
www.nature.com/icb
REVIEW
Complement and the central nervous system: emerging
roles in development, protection and regeneration
Martin J Rutkowski, Michael E Sughrue, Ari J Kane, Steven A Mills, Shanna Fang and Andrew T Parsa
As expanding research reveals the novel ability of complement proteins to promote proliferation and regeneration of tissues
throughout the body, the concept of the complement cascade as an innate immune effector has changed rapidly. In particular,
its interactions with the central nervous system have provided a wealth of information regarding the ability of complement
proteins to mediate neurogenesis, synaptogenesis, cell migration, neuroprotection, proliferation and regeneration. At numerous
phases of the neuronal and glial cell cycle, complement proteins exert direct or indirect influence over their behavior and fate.
Neuronal stem cells differentiate and migrate in response to complement, and it prevents injury and death in adult cells in
response to toxic agents. Furthermore, complement proteins promote survival via anti-apoptotic actions, and can facilitate
clearance and regeneration of injured tissues in various models of CNS disease. In summary, we highlight the protean abilities
of complement proteins in the central nervous system, underscoring an exciting avenue of research that has yielded greater
understanding of complement’s role in central nervous system health and disease.
Immunology and Cell Biology (2010) 88, 781–786; doi:10.1038/icb.2010.48; published online 20 April 2010
Keywords: complement; CNS; development; protection; regeneration; proliferation
As a critical effector of immune defense, the complement cascade has
long been appreciated as a fundamental component of innate immunity.
Comprised of the classical, alternative, and mannose-binding lectin
pathways, the complement system includes a large family of proteins
with diverse immune functions. These include promotion of inflammation, opsonization of target surfaces, clearance of apoptotic and
necrotic cells, lymphocyte activation and amplification, and lysis of
foreign pathogens.1 Deficiency or dysregulation of complement proteins is associated with a number of autoimmune and rheumatological
diseases,2,3 highlighting the widespread importance of the complement cascade in fundamental immune processes. In addition to its
immune characteristics, the complement cascade has recently been
implicated in a variety of proliferative and regenerative activities. A
growing body of evidence shows that complement proteins
participate in bone and cartilage development,4–8 angiogenesis,9–11
hematopoietic stem cell engraftment,12–14 amphibian limb and eye
regeneration,15,16 and liver regeneration.17–19
Similar complement-mediated proliferative phenomena can be seen
in the central nervous system (CNS), an organ system that has been
heavily studied for its myriad interactions with the complement
cascade (Figure 1). Initially, research examined its interactions with
the CNS through the prism of innate immunity, focusing mostly on
its potential to exacerbate neuroinflammation. Such complementmediated ‘collateral damage’ was assumed to be a secondary effect
of its participation in injury response, and numerous studies have
verified that complement cascade inhibition decreases injury in
ischemic, infectious, and inflammatory diseases.20,21
Recent attention to the complement cascade’s role in proliferation
and regeneration has challenged the view that it is solely injurious to
the CNS; instead, the complement cascade maintains a somewhat
paradoxical role as it has been implicated in both injury pathogenesis and protection.22 This apparent contradiction may not be
so inexplicable given our expanding understanding of the complex
roles of complement. In addition to promotion and participation
in neuroinflammation following injury, in vitro and in vivo experiments have revealed that complement proteins influence stem cell
maturation, cellular migration, synaptogenesis, growth factor induction, activation of anti-apoptotic and pro-survival signaling molecules
and neuroprotection from cytotoxic agents.
In the following review, we summarize the current literature
regarding the developmental, protective and regenerative role of the
complement cascade in the central nervous system.
Complement proteins and receptors are present in the central
nervous system
Complement protein synthesis has been appreciated in the nervous
system for over two decades.23 Subsequent discoveries have indicated
that neurons and glia produce an almost complete set of complement
proteins,20,24,25 an important finding given that the blood–brain
barrier largely excludes entry of such plasma products.24 The discovery
of this expansive production and distribution of complement raised
questions regarding the traditionally held view that its main role in
the CNS is defense against meningococcal meningitis. Meningococcal
infections are a known sequela of C5-9 deficiency, as these complement
Department of Neurological Surgery, University of California at San Francisco, San Francisco, CA, USA
Correspondence: Dr AT Parsa, Department of Neurological Surgery, University of California at San Francisco, 505 Parnassus Ave, San Francisco, CA 94143, USA.
E-mail: [email protected]
Received 15 October 2009; revised 22 February 2010; accepted 1 March 2010; published online 20 April 2010
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MJ Rutkowski et al
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Figure 1 The complement cascade includes the classical, alternative and mannose-binding lectin pathways. Each pathway is activated and amplified by
unique stimuli, but they eventually converge when complement protein C3 is cleaved into its C3a and C3b split products, leading to formation of the C5
convertase, production of C5 split products C5a and C5b, and terminal formation of the membrane attack complex (MAC). Exciting new research has
indicated that complement proteins and their receptors are present in neuronal and glial tissues in the central nervous system (CNS), facilitating diverse
proliferative activities including cellular development and maturation, protection from injury and regeneration. MBL, mannose-binding lectin; MASP,
mannose-binding lectin associated serine proteases.
proteins are integral to the membrane attack complex (MAC) and
the body’s ability to lyse the Gram-negative cell wall of Neisseria
meningitidis.2,26
Mounting evidence has shown a similarly widespread presence of
complement receptors throughout the nervous system.27–29 In one
study, mRNA expression for C3a receptor (C3aR) and C5a receptor
(C5aR) could be seen across most areas of the CNS, including the
cerebral cortex, cerebellum, medulla, basal ganglia, thalamus, hippocampus, corpus callosum and spinal cord.30 Other studies using
techniques such as immunohistochemistry and flow cytometry
have corroborated protein level expression of neuronal and glial
complement receptors.28,29,31
The complement cascade in neurogenesis and synaptogenesis
Research into the interactions of complement proteins with their
CNS receptors has yielded a wealth of information regarding
their developmental functions (Figure 2). In one study, C3aR was
discovered on murine neural progenitor cells and immature neurons
in vivo.32 Mice lacking the C3a complement fragment, C3aR, or those
exposed to a C3aR antagonist showed greatly inhibited neurogenesis
Immunology and Cell Biology
following ischemic injury.32 Antagonism of C3aR caused decreased
numbers of migrating neuroblasts and newly formed neurons
throughout the olfactory bulb and dentate gyrus subgranular zone.32
Furthermore, C3 / mice subjected to middle cerebral artery occlusion showed decreased numbers of neuroblasts in the ipsilateral
subventricular zone, a known reservoir of neural stem cells.33 The
authors extended this research to in vitro murine neural progenitor
cells, corroborating the presence of C3aR on their surface and
the multitude of developmental effects occurring upon C3a/C3aR
binding. Notably, C3a directly induced differentiation and maturation of neuronal progenitor cells.34
Interestingly, the authors found no evidence for C5a or C5aR
involvement in basal neurogenesis.34,35 Despite its apparent lack of
an effect on early neural precursors, C5a/C5aR binding does appear
to be important in the maturation of oligodendrocytes. A study
examining the expression of complement protein receptors on oligodendrocyte progenitor cells (OPCs) identified C5aR in rat and murine
OPCs. Downregulation of C5aR mRNA occurred concomitant to
OPC maturation into oligodendrocytes, raising the possibility that
C5aR mRNA levels may influence glial development and act as a
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Figure 2 Complement proteins wield considerable influence over the CNS via their effects on multiple phases of the neuronal and glial life cycle. In contrast
to their (1) promotion of neuroinflammation, complement proteins also facilitate cellular development, viability and regeneration from injury. (2) Research
has established that both neurons and glia produce a virtually complete set of complement proteins that may interact with their respective CNS complement
receptors. (3) C1q has been shown to increase synaptic pruning in developing mice via C1q deposition and subsequent classical cascade production of C3 in
synapses of the murine retina and dorsal lateral geniculate nucleus. (4) Binding of C3a/C3aR and C5a/C5aR in CNS progenitor cells can induce their
differentiation, maturation and migration. (5) Mature neurons and glia are protected from potentially lethal insults by various complement proteins, in part
through their stimulation of growth factor production and inhibition of pro-apoptotic proteins. (6) CNS regeneration has been particularly studied in
oligodendrocytes, which possess a remarkable ability to heal and remyelinate in response to C5 and the MAC. In addition, C3a and C5a induce growth factor
production in astrocytes and microglia, whereas (7) C5a induces proliferation of neuroblastoma cells.
marker of its progress.28 However, the study did not characterize cell
surface C5aR levels in mature oligodendrocytes, making it difficult to
determine the importance of differences in C5aR expression patterns
beyond the RNA level.
A different study found evidence of C3aR and C5aR in cerebellar
granule neurons of the developing rat brain.36 The post-natal rat
cerebellum is marked by a delicate balance between proliferation of
immature external granular layer neurons that migrate to the internal
granular layer, and apoptosis of excess cells that have not formed
appropriate synaptic connections.37 Receptors for C3a and C5a were
transiently seen in the external granule layer of newborn rats from day
of life 10 until 21, peaking at day 12.36 However, these receptors are
almost completely absent in the adult rat cerebellum, implicating a
purely developmental role.36 C5aR stimulation was found to inhibit
caspase-9 driven apoptosis of granular layer neurons.36
Follow-up research on the developmental roles of C5aR and C3aR
further delineated their importance in the rat cerebellum. C5aR
stimulation mediated neural progenitor proliferation and thickening
of the external granule cell layer, whereas C3aR stimulation conversely
decreased the thickness of the external granule layer and increased
the thickness of the internal granule layer.38 Because C3aR stimulation
did not result in increased apoptosis or maturation of granule cells,
the researchers surmised that it may have instead accelerated their
migration from the external to internal granule layer.38 Interestingly,
video-microscopy recordings confirmed this hypothesis with cultured
cells, showing increased velocity and distance covered by these
migrating neurons.38 Although cerebellar abnormalities are not seen
in animals deficient in C3aR and C5aR, it has been suggested that
these developmental effects may instead be critical in the setting of
cerebellar recovery following injury.38
Finally, recent evidence suggests that the classical cascade aids
synaptic pruning in the developing mouse brain.39 C1q is thought
to selectively accumulate in synapses, targeting them for pruning
through downstream cascades involving C3 and C5.40 In one particular study, mouse retinal ganglion cells were studied. Retinal ganglion
cell axons are known to project to eye-specific regions in the dorsal
lateral geniculate nucleus (dLGN). Through the process of synaptic
pruning, dLGN neurons reduce their axonal input from 10 to
only 1 or 2 retinal ganglion cell axons,41 enhancing these existing
connections and eliminating superfluous ones. Remarkably, researchers discovered that adjacent astrocytes strongly upregulate C1q when
exposed to retinal ganglion cells, resulting in deposition of C1q,
activation of the classical cascade, and further deposition of C3 on
synapses targeted for elimination in both the dLGN and the mouse
cortex.39 C1q deposition was largely absent in the inner plexiform
layer by day of life 15 and in the dLGN by day of life 30, but present in
both locations at day of life 5,39 corroborating its specific relevance in
synaptic development.
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MJ Rutkowski et al
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These findings are especially compelling in the context of neurodegenerative disease. C1q levels in microglia and neurons are upregulated by reactive astrocytes in response to CNS disease, including
Alzheimer’s disease, Huntington’s disease, glaucoma and amyotrophic
lateral sclerosis.39,42 Although unproven, the authors speculate
that increased levels of C1q may contribute to inappropriate
synaptic pruning in these diseases and thus contribute to their
pathophysiology.39
The complement cascade and neuroprotection
In addition to aiding development and maturation of glia and
neurons, experimental evidence indicates that complement proteins
can maintain a protective function over these cells in response to
several modes of injury. The proteins C3, C3a, C5, C5a and the MAC
appear to be particularly important in this prevention of CNS toxicity
and cellular apoptosis (Figure 2).
Animal models of CNS pathology have proven especially illustrative
of complement mediated neuroprotection. In one study, murine
astrocytes and neurons were exposed to kainic acid, resulting in far
greater injury among C5-deficient mice compared to C5-sufficient
mice.43 These results suggest a protective role for C5 in the murine
CNS. A follow-up study demonstrated the protective effects of C5a
specifically: kainic acid was co-infused with C5a, thereby decreasing
the extent of toxic injury via decreased neuronal apoptosis.44 The
authors discovered that C5a downstream effects include ERK1/2
inhibition45 of caspase-344 and glutamate receptor subunit 2 downregulation, consequently decreasing apoptosis.46
Beyond neuroprotection from toxic insult, C5 also has antiapoptotic functions in experimental autoimmune encephalomyelitis,
a mouse model of multiple sclerosis. In this model, C5 levels are
inversely correlated with apoptotic cells. When compared with
C5-deficient mice, C5-sufficient experimental autoimmune encephalomyelitis mice showed significantly fewer apoptotic oligodendrocytes
during recovery and healing.47 Additionally, C5 mediates myelination
through regulation of the genes for insulin-like growth factors,
insulin-like growth factor-binding proteins, and transforming growth
factor (TGF-b3).48 Insulin-like growth factors and insulin-like growth
factor-binding proteins have known importance via their effects on
OPC survival and differentiation, and are also capable of inhibiting
apoptosis of mature oligodendrocytes.48–50
Although the evidence is limited, C3a has also been shown to
possess neuroprotective capabilities. In vitro experiments were performed with neurons co-cultured with astrocytes. Under these specific
conditions, cell exposure to purified human C3a resulted in decreased
injury secondary to N-methyl-D-aspartate.51 Neuronal protection via
C3a occurred in a dose-dependent fashion, and appeared to be
mediated by adjacent astrocytes.51 C3a lost its anti-apoptotic effects
when neurons were cultured alone, deprived of serum or exposed to
AMPA or kainic acid.51
The MAC also shows the ability to promote CNS cell survival and
prevent apoptosis. For example, apoptosis of schwann cells52 and
oligodendrocytes53 is inhibited by the MAC. The presence of sublytic
doses of the MAC inhibits pro-apoptotic caspase-3 and caspase-8,54
BAD and BID,55 and TNF-a and FasL,56 whereas such doses protect
against programmed cell death by synthesizing anti-apoptotic bcl-255
and IGF-1.57
The complement cascade and neuroproliferation and regeneration
Evidence for the complement cascade’s neuroprotective effects is
tempered by research showing its deleterious inflammatory effects
on neurons and glia in injured states. These include demyelinating
Immunology and Cell Biology
disorders,56 neurodegenerative disorders,58 neurotrauma,58 and
vascular disorders including stroke and ischemic-reperfusion
injury.20,59 Yet an abundance of evidence shows that complement
proteins mediate CNS regeneration in a similarly diverse group of
disease processes (Figure 2).
The apparent contradiction of complement cascade injury and
regeneration in the CNS is aptly shown by the activities of the
MAC. Although lytic doses cause cellular membrane disruption with
secondary necrosis and apoptosis, sublytic levels of MAC induce
cellular proliferation in a wide variety of tissue types.26 MAC
induction of the oligodendrocyte cell cycle depends on activation
of mitogenic, proto-oncogenic, and anti-apoptotic intracellular
signaling pathways including MAPK,60 c-jun61,62 and PI3K/Akt,60,62
respectively.
Consequently, oligodendrocytes have proven an especially useful
target of study in the search for evidence of complement protein
induction of cellular proliferation.61,63 In addition to offering
evidence of complement-mediated prevention of oligodendrocyte
apoptosis, murine experimental autoimmune encephalomyelitis
has also been instrumental in showing complement’s regenerative
capacity. C5-deficient and C5-sufficient mice show salient differences
in chronic injury patterns. Whereas C5-deficient mice display marked
Wallerian degeneration, axonal loss and severe gliosis, C5-sufficient
mice show sparing of axonal degeneration with extensive concurrent
remyelination.64 Equally compelling, C5-sufficient mice display more
severe initial histopathological lesions but subsequently exhibit
more extensive axonal sparing and remyelination.64 It is possible
that this dichotomous response allows for more effective clearance
of injured cells and cellular material, creating a local environment
more conducive to healing and regeneration.56,64 This putative
importance in myelin clearance also appears to be an important
phenomenon in peripheral nerve regeneration.65
Astrocytes and microglia respond to complement cascade stimulation
with production of growth factors. Astrocytes respond synergistically to
C3a, C5a and interleukin-1b with production of nerve growth factor.66
Nerve growth factor has established importance in CNS development
and function,67 and is also known to be produced by astrocytes in
response to injury.68 Nerve growth factor upregulation and production
was similarly observed in microglia in response to C3a.69
In the search for evidence of C5aR in neurons, one study discovered
an intriguing finding: not only is C5aR constitutively expressed in
human and murine neurons, C5a binding promotes proliferation of
undifferentiated human neuroblastoma cells and protects terminally
differentiated human neuroblastoma cells from b-amyloid neurotoxicity.31 Mitogenesis was stimulated in a dose-dependent fashion, and
appears to be partially mediated via protein kinase C activation and
NF-kB. Conversely, C5a had no proliferative effects on terminally
differentiated neuroblastoma cells, although it did increase their
viability secondary to neuroprotective effects against b-amyloid toxicity.31 These results raise the intriguing possibility that complementmediated proliferation and regeneration may extend to neoplastic cells
in addition to terminally differentiated CNS cells.
CONCLUSION
With increasing evidence of the complement cascade’s developmental,
protective and proliferative functions in the CNS, it is becoming clear
that complement proteins can no longer be thought of as innate
immune effectors solely responsible for inflammation and tissue
cleanup. Exciting work has ascribed a wealth of new functions to
the complement cascade that implicate it in many phases of CNS cell
life. The complexity of complement’s effects on stem cells, neurons,
Complement and the central nervous system
MJ Rutkowski et al
785
glia and injured tissues offers enormous potential in the search for
new mechanisms by which to attenuate its deleterious CNS effects and
promote its regenerative properties.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGEMENTS
Martin Rutkowski received a grant from the Doris Duke Charitable Foundation. Dr Sughrue received a National Research Service Award from the National
Institutes of Health. Ari Kane received a grant from the Howard Hughes
Medical Institute. Dr Parsa was partially funded by the Reza and Georgianna
Khatib Endowed Chair in Skull Base Tumor Surgery.
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