Download Microglia and neurodegeneration C Cummingham

GLIA 61:71–90 (2013)
Microglia and Neurodegeneration: The Role of Systemic
Inflammation
COLM CUNNINGHAM*
School of Biochemistry and Immunology and Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland
KEY WORDS
systemic; inflammation; infection; microglia; priming; phenotype switching; delirium; dementia; Alzheimer’s disease;
Parkinson’s disease; prion; ALS
ABSTRACT
It is well accepted that CNS inflammation has a role in the
progression of chronic neurodegenerative disease, although
the mechanisms through which this occurs are still unclear.
The inflammatory response during most chronic neurodegenerative disease is dominated by the microglia and mechanisms by which these cells contribute to neuronal damage
and degeneration are the subject of intense study. More
recently it has emerged that systemic inflammation has a
significant role to play in the progression of these diseases.
Well-described adaptive pathways exist to transduce systemic inflammatory signals to the brain, but activation of
these pathways appears to be deleterious to the brain if the
acute insult is sufficiently robust, as in severe sepsis, or
sufficiently prolonged, as in repeated stimulation with robust doses of inflammogens such as lipopolysaccharide
(LPS). Significantly, moderate doses of inflammogens produce new pathology in the brain and exacerbate or accelerate features of disease when superimposed upon existing
pathology or in the context of genetic predisposition. It is
now apparent in multiple chronic disease states, and in
ageing, that microglia are primed by prior pathology, or by
genetic predisposition, to respond more vigorously to subsequent inflammatory stimulation, thus transforming an
adaptive CNS inflammatory response to systemic inflammation, into one that has deleterious consequences for the
individual. In this review, the preclinical and clinical
evidence supporting a significant role for systemic inflammation in chronic neurodegenerative diseases will be discussed. Mechanisms by which microglia might effect neuronal damage and dysfunction, as a consequence of systemic
stimulation, will be highlighted. V 2012 Wiley Periodicals, Inc.
counter peripheral inflammatory conditions such as
rheumatoid arthritis, the likely contribution of systemic
inflammation to the deterioration of brain function has
been little considered. We have known for many years
that systemic inflammation influences brain function.
Our own behavioral responses to simple infections demonstrate that inflammatory mediators can signal to the
brain to evoke significant changes in our behavior and
in our metabolism. These changes are mostly adaptive:
reorganizing our priorities and preserving energy to
mount a fever and fight infection, while suppressing
social and motor activity and isolating ourselves from
the rest of the herd. However, there is now considerable
evidence to suggest that systemic inflammation can
have deleterious consequences for the brain if the
inflammation is sufficiently severe, or if the brain shows
vulnerabilities due to genetic predisposition, ageing, or
neurodegenerative disease. This connection between the
brain and systemic inflammation heralds new ways in
which microglia may contribute to brain pathology. In
this review, the author will discuss the accumulating
evidence, from both preclinical and clinical studies, that
systemic inflammation negatively impacts on chronic
neurodegenerative disease. The focus of the review, in
keeping with the theme of this issue of GLIA, will be
the role of the microglia in these processes, but the clinical manifestations of systemic inflammatory insults will
remain the ‘‘litmus test’’ of the relevance of the phenomenon of systemic influence on brain deterioration.
Microglial Activation in Chronic
Neurodegeneration
C
INTRODUCTION
It is widely accepted that microglial activation contributes to neurodegenerative disease, but the mechanisms
by which this occurs remain elusive. The repeated observation that long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) protects against subsequent development of Alzheimer’s disease (AD) (Vlad et al., 2008)
and Parkinson’s disease (PD) (Chen et al., 2005) has
fuelled the idea that inflammation contributes to neurodegeneration and microglial cells have obviously been
assumed to be the most likely culprit. However,
although NSAIDs have generally been administered to
C 2012
V
Wiley Periodicals, Inc.
It is obviously not possible to discuss here, en masse,
the huge literature on microglial activation in neurodegeneration that has emerged in the last two decades.
However, it is useful to identify commonalities in microglial responses in neurodegenerative pathologies before
examining how systemic inflammation alters these. Macrophage biology nomenclature has moved in recent years
from the designation of macrophages as simply classiGrant sponsor: Wellcome Trust.
*Correspondence to: Colm Cunningham, School of Biochemistry and Immunology
and Trinity College Institute of Neuroscience, Trinity College, Dublin D2, Ireland.
E-mail: [email protected]
Received 20 February 2012; Accepted 17 April 2012
DOI 10.1002/glia.22350
Published online 6 June 2012 in Wiley Online Library (wileyonlinelibrary.com).
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cally (M1) or alternatively activated (M2), toward the
recognition of macrophage plasticity and of a dynamic
spectrum of activation states that can cover observed
phenotypes including classically activated, wound-healing, and regulatory macrophages (Mosser and Edwards,
2008). Likewise, microglial cells have now moved on
from older, binary, classifications of ‘‘quiescent’’ and
‘‘activated.’’ In addition to macrophage activation simply
by exogenous (pattern associated molecular patterns;
PAMPs) or endogenous (danger associated molecular
patterns; DAMPS) toll-like receptor (TLR) ligands, one
can define classically activated macrophages (M1) as
being activated by lipopolysaccharide (LPS), in combination with the Th1 cytokine interferon-g (IFN-g), to produce a robust proinflammatory profile including interleukin-1b (IL-1b), IL-12, tumour necrosis-a (TNF-a),
and inducible nitric oxide synthase (iNOS). Alternatively
activated macrophages (M2a) are driven by the influence
of IL-4 and IL-13, typically from Th2 cells, resulting in
an anti-inflammatory, profibrogenic profile. The M2b
phenotype is driven by immune complex formation and
TLR or IL-1b activation. Deactivated macrophages
(M2c) are typically influenced by transforming growth
factor-b (TGF-b), glucocorticoids, IL-10, or CD200 and
express relatively low levels of MHC Class II and elevated prostaglandins, contributing to the suppression of
proinflammatory cytokines. Given the influence of T
cells on these peripheral macrophage phenotypes and
the relative paucity of T cells in chronic neurodegenerative disease, it is reasonable to ask whether this nomenclature can be imposed on the brain: do microglial cells,
conform to M1, M2 (and M2 a,b,c) phenotypes during
neurodegenerative disease? In the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS), classically activated M1 phenotypes are well
described and IL-4 has also been shown to induce an
alternatively activated phenotype in microglial cells
(Ponomarev et al., 2007). Since Th2 cells are known to
be present in the brain in significant numbers in EAE,
this is a plausible route to the M2a phenotype. However,
though IL-4 can have a marked influence on microglial
activation when directly applied to the brain (Lyons
et al., 2007), there remains little direct evidence for IL-4
and IL-13 expression in the brain during other chronic
neurodegenerative diseases. With respect to the M1 phenotype, studies with intracerebral LPS have shown that
microglia can clearly adopt an innate activation/M1 phenotype. However, this phenotype is not similar to profiles during most models of chronic neurodegenerative
disease in that levels of proinflammatory cytokines
induced in chronic disease are much lower than those
induced by LPS, despite the universal observation of significantly increased numbers of microglial cells during
disease (Fig. 1). In that context one has to question the
relevance of using substantial injections/infusions of
LPS into the brain to model chronic neurodegenerative
disease, as has been done for both Alzheimer’s (HaussWegrzyniak et al., 1998) (0.25 lg/h i.c.v. for 28 days) and
Parkinson’s diseases (Herrera et al., 2000) (2 lg LPS,
intranigral). Likewise using severe sepsis/septic shock to
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produce pathological features of AD and PD, may have
told us that particular regions of the brain are particularly sensitive to inflammatory damage (Qin et al.,
2007), but they are unlikely to reflect the pathogenesis
in those patients who suffer from this disease. It is significant that these models still provide the most unambiguous evidence of M1 microglial phenotypes and of a
disease course that is amenable to anti-inflammatory
treatment (Hirsch and Hunot, 2009). Unlike the very
substantial inductions of proinflammatory genes after
LPS, studies in transgenic models of AD have reported
expression of IL-1b and iNOS of approximately one to
threefold, and protein levels have not often been
reported (Schwab et al., 2010). There are many potential
difficulties in the reliable assessment of cytokine expression in the CNS, as recently discussed (Ransohoff and
Perry, 2009). Notwithstanding this, there is a continuing
perception that macrophages in neurodegenerative disease are of the M1, classically activated phenotype. A
recent study of both human AD cases and AD mouse
models showed evidence for limited M1 polarization
(twofold increase in TNF-a mRNA, and no change in
iNOS or IL-1b), alongside fourfold induction of the M2
marker YM1 and lesser inductions of arginase-1 and
mannose receptor. These patterns were largely replicated in human AD frontal lobe samples (Colton et al.,
2006). The demonstration that amyloid-b (Ab) can activate the NLRP3 inflammasome (Halle et al., 2008) has
sustained the argument that IL-1b is a key player in
AD pathogenesis, but it is worth noting that even in
that study the inflammasome was first ‘‘primed’’ by
treating with LPS. Thus without the LPS-induced supply of pro-IL-1b, Ab appears to show limited capability
to produce significant IL-1b. Such studies probably oversimplify the relationship between Alzheimer’s disease
and IL-1b, but given the frequency of co-morbidity in
the ageing population, the requirement for ‘‘multiple
hits’’ (LPS 1 Ab) to bring about an M1 phenotype in the
brain is perhaps not surprising, and is a key point for
discussion below.
One feature that has consistently been reported is
that CCL2 (formerly MCP-1), with or without detectable
TNF-a, appears consistently up-regulated in multiple
models of chronic neurodegeneration: AD (Sly et al.,
2001), PD (Sriram et al., 2006), ALS (Henkel et al.,
2004), and prion disease (Felton et al., 2005), and this is
entirely consistent with the inflammatory component of
these diseases being dominated by myeloid lineage cells.
MCP1/CCL2 is a key chemokine for microglial activation
and monocyte chemoattraction (Fuentes et al., 1995).
Though peripheral monocytes have been shown to infiltrate the brain and migrate to amyloid plaques (Simard
et al., 2006) after whole body irradiation, it is apparent
that when the brain is ‘‘protected’’ using a lead helmet
during these irradiation experiments, bone marrowderived macrophages do not infiltrate the brain in large
numbers (Mildner et al., 2011). Irrespective of this, we
remain unclear about the provenance of CCL2 expression and microglial activation in AD models: CCL2 overexpression increased microglial number and exacerbated
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Fig. 1. Microglial activation in chronic neurodegenerative disease is
muted. A comparison of microglial number, morphology, cytokine synthesis, and phagocytic function in normal animals, 16-month-old APP/
PS1 double transgenic mice, ME7 prion-diseased animals at 18 weeks
postinoculation and normal animals injected i.c. with 2 lg LPS. Top
panel: IBA-1 labeling reveals small clusters of microglia in the APP/
PS1 brain, but not a generalized microgliosis. The ME7 brain shows
uniform microgliosis throughout the hippocampus. LPS i.c. shows relatively sparse microglia and activation of the cerebrovascular endothelium. Table shows microglial quantification (# number of cells arbitra-
rily set to one to allow other groups to be shown as fold differences)
and quantitative PCR and ELISA data for IL-1b, TNF-a, and TGFb1.
Where ELISA data are shown in pg/mL, data have been obtained in the
authors laboratory and where shown as 6 these have been summarized
from a review of the literature. Bottom panel: COX-1 positive microglia in
the APP/PS1 brain can be seen surrounding an Ab plaque, while IBA-1
positive microglia in the prion-diseased brain can be seen completely
engulfing an apoptotic, TUNEL-positive, cell. These microglia remain IL1b-negative during this activity. (Reproduced with permission from
Hughes et al., GLIA, 2010, 58, 2017–2030,'Wiley-Blackwell).
disease (Kiyota et al., 2009) while CCR22/2 mice
crossed with Tg2576 (El Khoury et al., 2007) or APP/
PS1 (Naert and Rivest, 2012) showed impaired microglial accumulation and accelerated Ab deposition. However, microglial depletion experiments showed that removal of microglial cells for 4 weeks had no impact on
Ab deposits (Grathwohl et al., 2009) and it has recently
been shown that CCR2 deficiency impairs the ability of
PVMs, rather than microglia, to clear Ab (Mildner et al.,
2011), consistent with older reports that microglia are
simply not efficient at Ab clearance (Wisniewski et al.,
1991). Thus microglial activation in AD models is not
typified by a robustly activated and phagocytic phenotype. In this regard it is also significant that both inducible over expression of IL-1b in the APP/PS1 AD model
(Shaftel et al., 2007) or intrahippocampal LPS injection
(DiCarlo et al., 2001; Herber et al., 2004) significantly
improve Ab clearance, indicating that phenotypic
switching occurs in these mice upon secondary stimulation. Thus, although there is some evidence that these
phenotypes can shift from M2-type to more M1-like with
advancing age in AD transgenics (Jimenez et al., 2008)
it is clear that microglia are not operating in a fully M1
mode during chronic neurodegenerative disease per se.
The microglia have potential that is somehow suppressed. Microglia in prion disease also show only limited evidence of IL-1b and TNF-a expression, but
instead appear to be dominated by TGFb1 and PGE2
(Cunningham et al., 2002; Minghetti et al., 2000; Walsh
et al., 2001). This is consistent with the idea of a microglial cell engaged in the phagocytosis of apoptotic cells,
as is known to occur in prion disease and other neurodegenerative diseases. Peripheral macrophages engaged in
phagocytosis of apoptotic cells synthesize TGFb1 and
PGE2 and directly suppress expression of IL-1b and
TNF-a (Fadok et al., 1998) and we have now demonstrated that microglial cells remain IL-1b negative while
phagocytosing apoptotic cells (Fig. 1) in the hippocampus, in vivo (Hughes et al., 2010). It seems reasonable to
suggest that these microglia show features of the M2c
phenotype, but as will be discussed below, these phenotypes are not static but change with subsequent stimulation. The cells depicted in Fig. 1 are also consistent with
the demonstration of a role for the inhibiting receptor
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TREM2 in noninflammatory phagocytosis (Takahashi
et al., 2005), thus controlling inflammation in the midst
of neurodegeneration. Recent data that prion disease progression is more rapid in mice lacking Mfge8, an important protein linking apoptotic cells to the phagocytic machinery (Kranich et al., 2010) would appear to underline
the importance of effective clearance of apoptotic bodies.
Phenotypic Switching: Microglia are Primed by
Neurodegenerative Disease
Microglial activation, per se, may contribute to damage during chronic neurodegeneration but it is essential
to make the point that the profile of microglia in most
models of chronic neurodegenerative disease is muted
compared with what these cells can produce (Fig. 1),
and it seems reasonable to suggest that their default
mode is the clearance of debris with the minimal disturbance and damage to the tissue. There is clearly a
level of control exerted by other factors that allows these
cells to remain in a state of partial activation. We discovered that this state of activation in prion disease
could be significantly altered by subsequent systemic
inflammatory insults, and that this had functional and
pathological consequences for the brain. These first
experiments lead to the concept of microglial priming:
that the brain is ‘‘primed’’ by chronic CNS disease, to
show exaggerated responses to subsequent inflammatory
stimulation, whether of a systemic or central origin
(Combrinck et al., 2002) and we later demonstrated that
it was the microglia that are primed and are responsible
for this exaggerated response (Cunningham et al.,
2005b). The terminology we adopted at that time (Perry
et al., 2007) was derived from the original description of
peripheral macrophage priming (Johnson et al., 1983)
because our observations matched those of the original
studies in that when the macrophage was primed, by
IFN-g in the original studies, the cells then responded
to subsequent activation with LPS by expressing significant levels of iNOS (Cunningham et al., 2005b). Direct
application of LPS to the normal brain induced detectable IL-1b, but iNOS was absent and subsequent neutrophil infiltration was very limited. However, application
of LPS to the prion-diseased brain produced abundant
microglial IL-1b and iNOS expression and overwhelming
neutrophil infiltration (Cunningham et al., 2005b). We
did not observe any consistent morphological change
between ‘‘primed’’ and phenotypically switched microglia. Microglial cells of the diseased brain thus undergo
phenotypic switching upon subsequent inflammatory
stimulation, changing from perhaps an M2c phenotype
to a more M1 phenotype, without obvious morphological
change. We showed, in the same study, that this exaggerated microglial IL-1b response could also be demonstrated after systemic inflammatory activation with
LPS, but this intracerebral, proof of concept, experiment
remains the clearest in vivo demonstration that it is the
microglial cell, rather than some other link in the chain
linking the periphery to the brain, that is responsible
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for the exaggerated CNS inflammatory response. Since
those experiments, exaggerated inflammatory responses
to systemic inflammation have been reported in ageing
and in models of Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, ALS, stroke, and Wallerian
degeneration. Thus it seems likely that priming is a
generic phenomenon of the microglial response to pathology. Differences in the nature of activation during
the primary pathology may lead to different manifestations postsystemic insult, but these insults certainly
have consequences for the underlying disease process.
Since these primed cells reside in areas of existing pathology, the deleterious effects of systemic inflammation
are ‘‘targeted’’ to brain regions that are already vulnerable, thus exacerbating functions already impaired by disease.
Our use of the term priming to describe the nature of
the microglial phenotype in the neurodegenerating brain
arose independently from, but parallel with, the idea of
priming of the inflammasome and this leads to some
potential for confusion in the nomenclature. IL-1b synthesis and secretion is achieved via cleavage of an inactive form of the protein, pro-IL-1b, by cytosolic protein
complexes called inflammasomes. Like the concept of
microglial priming and phenotype switching, inflammasome activation is also a two step process involving
‘‘priming’’ and ‘‘activation,’’ but in inflammasome studies
LPS has been typically used to ‘‘prime’’ the inflammasome (i.e. provide the signal for the transcription of proIL1b) and a second stimulus can then activate the
inflammasome to allow caspase-1 to cleave this pro-IL1b and allow secretion of the active cytokine (Eisenbarth
and Flavell, 2009). Conversely the author, and others,
described that some aspect of neurodegeneration, ageing
or amyloidosis ‘‘primed’’ the microglia, whereupon LPS
could now trigger phenotypic switching toward an M1
phenotype. So, are there similarities between microglial
priming and inflammasome priming (Fig. 2), or is this
just an unfortunate coincidence of nomenclature? A
study of Ab peptide effects on primary microglial cultures showed that Ab was capable of activating the
NALP3 inflammasome to allow synthesis of active IL-1b
and release of NO (Halle et al., 2008). This model proposed that Ab was phagocytosed by microglia, and that
cathepsin B was released from lysosomes and activated
the inflammasome. Thus fibrillar amyloid would appear
to be an activator of the inflammasome. However, it is
important to note that microglial cells were ‘‘primed’’
with LPS in order to facilitate this IL-1b release and
action: fibrillar amyloid by itself did not result in pro-IL1b synthesis. This would suggest that if Ab is to induce
this robust IL-1b response, another stimulus would also
be required. While experimental studies in inflammasome biology typically first ‘‘prime’’ with LPS and then
‘‘activate,’’ it is possible that the inflammasome could be
assembled by a trigger such as Ab, and that the pro-IL1b signal could be supplied, at a later time in disease,
by some other stimulus such as LPS, arising from a systemic infection. Inflammasome experiments have also
been performed in cells isolated from the G93A SOD1
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Fig. 2. Macrophage, microglial, and inflammasome priming. The
original description of macrophage priming was simply that prior exposure to IFN-g resulted in more robust responses to subsequent LPS exposure, with only the combination of both stimuli inducing iNOS.
Microglial activation was so named since it replicated this iNOS synthesis after microglia ‘‘primed’’ by neurodegenerative disease showed exaggerated responses to LPS. The priming factors are not clear but may
include exposure to Ab and other amyloid proteins, neurodegenerative
debris, complement, glucocorticoids, or the loss of inhibitory influences
such as TREM2, CXCR1, CD200R binding interactions, loss of tonic in-
hibition by neurotransmitters such as noradrenaline and acetylcholine
and genetic susceptibility via failure to express inflammatory repressors
such as Nurr1 and putatively Parkin. The term inflammasome priming
arose in parallel but referred to the induction of pro-IL-1b transcription
and translation as ‘‘priming’’ and the assembly of the inflammasome
and generation of activated caspase-1 as ‘‘activation.’’ There is some evidence that Ab and mutant SOD1 can activate the inflammasome, but a
priming stimulus to induce pro-IL-1b is also required and its identity in
neurodegenerative disease is not known. Most experimental studies of
inflammasome activity induce priming by pretreating with LPS.
mutant mouse model of ALS, showing that endocytosed
mutant SOD1 can activate caspase-1 activation and IL1b secretion, dependent on ASC but independent of
NLRP3 activation (Meissner et al., 2010). The authors
state that this can occur without prior priming with
LPS, but their data clearly show that a robust pro-IL-1b
signal is already present in all microglial cultures, thus
obviating the need for treatment with LPS to provide
the pro-IL-1b signal. It will be necessary to test the hypothesis that mechanisms of microglial priming and
phenotype switching overlap significantly with inflammasome priming and activation, but for the remainder
of this article, the term priming will refer to microglial
priming as originally described (Perry et al., 2007).
Danger-associated molecular patterns (DAMPs) such
as HMGB1, nucleic acids, hyaluronon, a-synuclein, etc.
may also be generated during chronic disease and may
activate TLRs to transcribe pro-IL-1b via NF-jB activation, although in general the evidence for these processes is much stronger for acute insults such as stroke
and indeed substantia nigra cell death induced by mito-
chondrial toxins (Gao et al., 2011b), where significant
necrosis and release of cellular contents occurs (Chen
and Nunez, 2010).
So what, during chronic neurodegenerative disease,
might be the priming factor or factors? There have been
a number of interesting recent studies in this regard. It
has recently been shown that deletion of the C3 convertase regulator complement receptor 1-related protein y
(Crry) leads to microglial priming, as measured by dramatically enhanced responses to systemic LPS (Ramaglia et al., 2012). This priming was abolished in Crry/C3
double knockout animals, implicating expression of C3
as a key factor. The proposal arising from the study is
that dysregulation of the complement system, as can
occur in AD (McGeer and McGeer, 2002), multiple sclerosis (Ramaglia, 2012), and indeed in the ME7 model of
prion disease (Cunningham et al., 2005a), leads to
increased C3 and its cleavage products C3b and iC3b
which bind to the microglial cell surface and consequently induce priming. This is an attractive explanation for microglial priming, because the complement
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mediated phagocytosis of apoptotic cells, via C1q, C3b,
or iC3b opsonization, is an important mechanism of
clearing debris in a relatively anti-inflammatory or ‘‘nonphlogistic’’ manner. As stated above, microglial activation is relatively muted in several models of neurodegenerative disease and we have observed that microglia
engaged in phagocytosis of apoptotic cells in vivo, during
prion disease, remain IL-1b-negative (Hughes et al.,
2010). However, the cleavage of C3 that occurs during
complement-mediated opsonization would appear to
leave these phagocytes susceptible to further activation.
In the ME7 prion disease model a number of Fcg
receptors have been shown to be elevated and while disease progresses normally in g chain knockout mice, the
ability to synthesize CNS IL-1b in response to systemic
LPS was significantly impaired (Lunnon et al., 2011).
This indicates that the Fcg chain has an important role
in phenotypic switching of the microglial population.
In addition, it has been clear for some time that molecular signatures of the brain microenvironment contribute to suppressing microglial activation. There is an
ever-growing list of molecules that can down-regulate
microglial function via direct interaction between neuronal cell surface markers such as CD200, fractalkine
(CX3CL1), and their corresponding receptors on microglia (CD200R, CX3CR1, and TREM2) among several
others. The loss or deletion of these molecules has been
shown in several studies to increase levels of microglial
activation. Consistent with the observation that aged
animals show primed microglial responses to secondary
stimulation with LPS (Godbout et al., 2005), it has been
shown that CD200 expression on neuronal dendrites
decreases with age (Ojo et al., 2011) and glia prepared
from CD2002/2 mice show heightened responses to LPS
stimulation (Costello et al., 2011). Likewise, decreased
expression of CX3CL1 has been shown in aged mice
(Wynne et al., 2010) and deletion of its receptor
(CX3CR1) increases the susceptibility of these mice to
LPS-induced CNS inflammation and sickness behavioral
responses. However, it is important to note that systemic
IL-1b was also enhanced in the CX3CR1 mice (Corona
et al., 2010), suggesting that loss of these receptors may
produce a heightened inflammatory responsiveness
throughout the body.
It has been recognized for some time that neurotransmitters can exert tonic inhibition on inflammatory activation. Noradrenaline can exert anti-inflammatory
effects on microglia via the b2 adrenergic receptor
(Heneka et al., 2010; O’Sullivan et al., 2009), and the removal of noradrenaline’s influence on cortical and hippocampal microglia in an animal model of AD, via lesioning of the locus ceruleus using the toxin dsp4, showed
that Ab pathology was exacerbated in the absence of
NE’s influence. Furthermore, in vitro characterization
suggests that microglial proinflammatory cytokine
responses to Ab are suppressed by NE administration
(Heneka et al., 2010). Acetylcholine can exert antiinflammatory actions via the nicotinic a7 receptor, and
although this is best characterized in the viscera, where
vagal ACh outflow suppresses systemic inflammatory
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responses to LPS (Tracey, 2009), there is evidence that
microglia also bear this receptor and can be influenced
by nicotine to suppress cytokine responses (De Simone
et al., 2005). Whether endogenous ACh actually exerts
this effect on microglia in vivo is not clear. We have
recently failed to find evidence of microglial priming after selective lesioning of the basal forebrain cholinergic
system (Field et al., 2012). While these data argue
against a role for endogenous acetylcholine in microglial
suppression, these lesions were deliberately limited in
extent (approximately 20% ACh depletion) and more
complete lesions may indicate an inhibitory role of endogenous ACh.
Continuing with the idea of suppression of microglial
activation by constitutive factors in the brain, some
potential players in Parkinson’s disease have recently
been shown to fulfill such a role. Nurr1, rare mutations
in which are associated with familial PD, can inhibit
expression of proinflammatory molecules by microglia
and astrocytes in response to LPS, and Nurr1 suppression using intranigral injections of a lentiviral-encoded
shRNA against Nurr1, showed considerable protection
against LPS-induced nigral neuronal death (Saijo et al.,
2009). Mechanistically, this is explained by the binding
of Nurr1 to the NF-jB p65 subunit and recruitment of
the coREST co-repressor complex and enhanced clearance of NF-jB with consequent transcriptional repression. Inflammation-induced down-regulation of another
familial Parkinson’s disease-related protein, parkin, also
leads to exaggerated responses to LPS, albeit in peritoneal macrophages (Tran et al., 2011). However, in other
studies by the same laboratory, Parkin2/2 mice are
more sensitive to inflammation-induced damage but do
not appear to show exaggerated CNS inflammatory
responses to the chronic LPS dosing regime in that
study (Frank-Cannon et al., 2008). Thus, it remains
unclear whether parkin deletion or suppression during
inflammation leads to microglial priming. In contrast to
these suppressions of constitutive proteins, the generation of extracellular a-synuclein, appears to be a significant priming factor for microglia as characterized in
recent studies. Extracellular a-synuclein, injected
directly into the substantia nigra provoked a robust
proinflammatory response and when animals were challenged with systemic LPS, 18 h later, levels of proinflammatory mediator synthesis were equivalent to those
induced by centrally administered LPS (Couch et al.,
2011). Centrally administered 6-OHDA can also prime
microglia, presumably secondary to nigral neuronal
death (Depino et al., 2003). There are, therefore, several
possible routes to priming in the Parkinson’s diseased
brain.
With respect to AD models, mice carrying a knock in
of the familial AD mutation M146V in presenilin 1,
showed exaggerated responses to systemic LPS, which
included augmented IL-1b, TNF-a, and iNOS synthesis
(Lee et al., 2002). Whether this was related to the aberrant PS1 or the increased Ab deposition was not directly
interrogated but exaggerated responses were apparent
in isolated microglial cells but not in splenocytes, sug-
SYSTEMIC INFLAMMATION AND CNS DISEASE
gesting the latter. Other in vivo studies in AD transgenics showed that proinflammatory cytokine profiles were
muted in disease per se and exaggerated by systemic
LPS challenge (Sly et al., 2001), perhaps indicating that
Ab plaques are themselves sufficient to prime microglia.
In ALS, isolated microglia carrying the G93A SOD-1
mutation show exaggerated proinflammatory responses
to LPS 1 IFN-g stimulation and this is associated with
increased expression of CCAAT/enhancer binding protein b (C/EBP/b), a transcription factor for which there
are binding sites in the promoter regions of proinflammatory genes including TNF-a, IL-1b, IL-6, and iNOS
(Valente et al., 2011). Increased nuclear translocation of
C/EBPb was seen in microglia of G93A SOD-1 mice
challenged i.p. with LPS, albeit at the very high dose of
200 lg LPS per mouse.
It is well known that glucocorticoids have immunosuppressive and anti-inflammatory actions, but it has gradually become clear that they can in some instances, particularly in the brain, lead to heightened inflammatory
responses to subsequent stimulation (de Pablos et al.,
2006; Munhoz et al., 2010). Recent studies have suggested that psychological stress, in vivo, primes microglia for exaggerated responses to LPS ex vivo and that
this is mediated by glucocorticoids, based on the ability
of both adrenalectomy and inhibition of GC receptor
function with the antagonist RU486 (Frank et al., 2012)
to prevent this primed response. The dysregulation of
the HPA axis is a frequent feature of neurodegenerative
and neuropsychiatric disease and thus elevated glucocorticoids may well contribute to microglial priming in a
number of settings, although this awaits verification in
in vivo models of disease. Thus, while the microglial glucocorticoid receptor may be important for limiting
inflammation in PD models (Ros-Bernal et al., 2011),
this could still lead to a microglial state vulnerable to
phenotypic switching.
Returning to the origins of the macrophage priming, it
seems appropriate to raise the possibility of Type I interferons (IFN a/b) as microglial priming factors. The authors
and others have shown that Type I IFNs are elevated by
neurodegenerative insults (Field et al., 2010; Khorooshi et
al., 2008; Stobart et al., 2007) and these molecules have
previously been shown to be capable of inducing priming
of peritoneal macrophages (Vadiveloo et al., 2000).
Finally it is worth considering whether it is sufficient,
for priming, to have a heightened, albeit low grade, systemic inflammatory state on an ongoing basis. It is well
established that chronic conditions such as obesity, diabetes, atherosclerosis, arthritis all have a systemic
inflammatory component (Yaffe et al., 2004). We consider the impact of chronic co-morbidities on established
disease later, but there is some evidence that these conditions themselves prime the brain (Drake et al., 2011).
77
state arise. Our experience of prion disease suggests
that microglial already show primed responses as early
as 12 weeks postinoculation with disease, before diseaseassociated cognitive changes are present (Murray et al.,
2012) and as disease progresses this priming appears to
become more robust (Cunningham et al., 2005b). In
Tg2576 mice, priming is not apparent at 6 months but is
demonstrable at 18 months (Sly et al., 2001). Notably
C3 expression is also increased in these older mice, perhaps implicating C3 as a key priming factor. There are
reports from other AD models of changes in phenotype
with ageing and whether these different states are differentially susceptible to phenotype switching upon subsequent challenge has not been widely investigated. In
the optic nerve crush model of Wallerian degeneration
in which significant myelin degradation and phagocytosis occurs over a prolonged period, microglia remain
primed for at least 28 days after the initial acute nerve
injury (Palin et al., 2008), and that microglial priming
persists in EAE lesions has recently been demonstrated
out to 6 weeks post-resolution of monophasic disease
onset (Moreno et al., 2011).
As for the time-course of cells after they become fully
activated: we have used LPS or poly I:C to show that
cells become activated to make IL-1b but this does not
appear to last long (Field et al., 2010; Murray et al.,
2012). There are, of course, downstream effects of these
patterns of induction and these may mean that the
‘‘wave’’ effectively lasts longer. There is certainly evidence that Fcg receptor changes are still evident at 24 h
post-LPS (Lunnon et al., 2011). However, there is little
evidence for a lasting M1 phenotype after either LPS i.c.
or i.p. One recent study showed a decreased responsiveness of primed microglia from the aged brain to IL-4
(Fenn et al., 2011) but there is little doubt that the
inflammatory wave post-LPS (at least at doses mimicking common infections) does resolve and microglia can
return to their pre-LPS phenotype, with acute cognitive
disruptions also resolving fully, at least at early stages
of underling disease (Murray et al., 2012). How this situation changes when the systemic inflammatory insult
is chronic or passes through innate and adaptive phases
is not clear. Evidence from some PD models, suggesting
that a single systemic insult with LPS is sufficient to
induce lasting iNOS and NADPH oxidase activity in
mice with a-synuclein mutations may reflect particularly
potent microglial activating qualities of a-synuclein (Gao
et al., 2011a).
Systemic Inflammation Contributes to Damage
and Dysfunction in Neurodegenerative Disease:
Evidence from Animal Models
Severe sepsis
Temporal Aspects of Priming
With respect to temporal aspects of microglial priming
questions as to the transience or permanence of this
Although the idea that systemic inflammation is a significant contributor to CNS pathology is a relatively new
one, brain damage resulting from severe sepsis is well
known to occur in humans and in rodents. Animal modGLIA
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els of sepsis, using doses of LPS of the order of 10 mg/kg
have shown evidence of robust CNS inflammation,
microglial iNOS expression, neuronal death, and longterm cognitive decline (Semmler et al., 2005, 2007).
Transgenic studies with iNOS2/2 mice demonstrated
an important role for iNOS in both cognitive deficits and
changes in presynaptic and postsynaptic molecules
(Weberpals et al., 2009). However, there may be other
mechanisms contributing to damage in such models:
markedly decreased cerebral metabolism using microPET imaging of glucose uptake (18FDG) has been demonstrated and this was associated with decreased cerebral blood flow and decreased alpha activity in EEG
(Semmler et al., 2008). Thus, robustly impaired brain
function may occur acutely as a result of decreased tissue perfusion and oxygenation, but inflammation would
appear to be a significantly contributor to subsequent
neuronal death and denervation. There have been a
number of studies in recent years in which these high
‘‘sepsis’’ doses have been used to replicate features of
neurodegenerative diseases such as Alzheimer’s disease
and Parkinson’s disease (Qin et al., 2007). It is important to draw a clear distinction between these high
doses and those used to simulate systemic infection as
generally experienced in the population.
Repeated dosing with LPS induces features of
neurodegenerative disease
There have also been several studies with multiple
doses of LPS administered to normal animals and animals with particular mutations. The group of Serge Rivest made repeated challenges with LPS (1 mg/kg every 2
weeks for a 3-month period) to induce markedly more
severe axonal pathology and progression of disease in
the G37RSOD1 mouse model of ALS (Nguyen et al.,
2004). It is noteworthy that there was no evidence of an
exaggerated acute inflammatory response in G37R mice
compared with wild type: in this instance, there is not
evidence of microglial priming, although LPS clearly
exacerbated the chronic inflammation associated with
disease per se. Another early study administered LPS
weekly for 12 weeks (150 lg/mouse/week) and found
increased APP expression and processing, leading to
increased intraneuronal generation of amyloidogenic Ab
(Sheng et al., 2003). One study used a regime of 7 consecutive days of LPS challenge (250 lg/kg), in naive
mice, to induce increased Ab1–42 generation and deposition of plaque material, probably via increased b- and gsecretase activities (Lee et al., 2008). In the triple transgenic model of AD, LPS treatment increased the severity
of Tau tangle pathology when administered at 500 lg/kg
twice weekly for 6 weeks (Kitazawa et al., 2005). LPSinduced Tau hyperphosphorylation could be blocked by
inhibiting the activity of cyclin-dependent kinase 5
(cdk5). In the 3xTg model of AD, twice-weekly injections
of LPS (250 lg/kg) for 4 consecutive weeks also
increased preplaque APP accumulation (intraneuronal
6E10 labeling) and this was TNF-a-mediated (McAlpine
GLIA
et al., 2009). Thus, LPS has typically been shown to alter APP processing and Ab deposition, but alternative
mechanisms by which LPS may alter disease course, via
microglial activation are discussed below.
A similar approach has been taken in the Parkinson’s
disease field. Although loss of function mutations in parkin are present in almost half of early onset PD cases,
parkin2/2 mice do not show typical features of Parkinson’s disease such as nigral neuronal loss. However,
parkin2/2 mice were shown to be more vulnerable to
inflammation-related nigral inflammation induced by
administration of LPS (250 lg/kg) twice weekly for 3 or
6 months to parkin2/2 mice (Frank-Cannon et al.,
2008). It should be noted that prolonged treatment with
LPS was sufficient to cause significant nigral loss even
in wild-type animals. Despite the interaction between
LPS and genotype with respect to nigral neuronal death
and beam walking abilities, there were remarkably limited differences in the neuroinflammation observed in
parkin2/2 1 saline, WT 1 LPS, and parkin2/2 1 LPS
groups. The inflammatory markers in this study were
examined only once, after 3 months of LPS treatment
but the data suggest that there are not primed microglial responses in the parkin2/2 mouse and neuronal
death may be more to do with an inherent vulnerability
of neurons of the parkin2/2 mice. Interestingly, 1 mg/
kg LPS administered once weekly for 4 months has exacerbated microglial activation but had no impact on neurological scores in an animal model of Huntingtons disease (Franciosi et al., 2012).
Though these repeated LPS models typically do not
use LPS doses as high as those used in studies of severe
sepsis, the dosing regime is nonetheless rather high or
rather prolonged and in some cases, both. There has not
typically been a rationalization of what these prolonged
LPS exposures are designed to mimic: multiple systemic
infections, chronic peripheral inflammatory disease, or
some other source of inflammation? It is known that animals can develop tolerance (Ziegler-Heitbrock, 1995)
and/or hypersensitivity (Greer and Rietschel, 1978) to
LPS depending on the dose and timing regime and consecutive systemic LPS challenges (for 4 days) are sufficient to completely ablate systemic TNF-a responses to
further systemic LPS, without inducing CNS tolerance
(Faggioni et al., 1995). Similarly, when multiple LPS
challenges are made in quick succession, CNS IL-1a,
TNF-a, IL-6, and MCP-1 responses are considerably exacerbated (Erickson and Banks, 2011). Given that the
repeated LPS approach is now frequently used in AD
and PD research, and has deleterious consequences for
disease, it is important to interrogate the way in which
the response to LPS changes upon multiple challenges.
Single LPS challenge exacerbates disease
Using a single challenge with LPS, to mimic a single
episode Gram-negative bacterial infection, is a conceptually simple way to interrogate the interaction between
systemic inflammation and chronic neurodegenerative
SYSTEMIC INFLAMMATION AND CNS DISEASE
disease. One early report showed that a single systemic
challenge with LPS, at 500 lg/kg, could alter expression
of APP but these authors did not examine disease per se
(Brugg et al., 1995). More recently, a single challenge
with LPS (500 lg/kg i.p., from Salmonella equine abortus), acutely increased neuronal apoptosis in the ME7
model of prion disease, but not in normal animals. (Cunningham et al., 2005b). This same dose, when administered just once at 15 weeks postinoculation with disease,
was sufficient to cause acute and reversible neurological
changes in ME7 and even after full recovery from acute
deficits, the LPS-treated ME7 animals developed progressive and irreversible neurological impairments earlier and with greater severity than ME7 animals not
treated with LPS (Cunningham et al., 2009). In studies
using the human A53T a-synuclein mutation in mice, a
single systemic challenge with 3 3 106 Endotoxin Units
(approximately 1 mg/kg) LPS was sufficient to induce
lasting iNOS and NADPH oxidase labeling and tyrosine
hydroxylase-positive neuronal loss (Gao et al., 2011a).
Also relevant to PD, using wild-type aged mice (20–22
months) a single challenge with LPS (200 lg/kg) was
sufficient to induce TH-positive neuronal death in the
substantia nigra (L’Episcopo et al., 2011), suggesting
that the aging brain becomes progressively more vulnerable even to common and proportionate environmental
stimuli.
Other systemic inflammatory stimuli
Though the majority of studies in this area have
been performed with LPS, other stimuli have been
assessed. In the 6-OHDA model of Parkinson’s disease
adenovirally-mediated systemic expression of IL-1b significantly exacerbated neuronal loss in the substantia
nigra and exacerbated motor symptoms (Pott-Godoy
et al., 2008). The inhibition of iNOS partially protected
against IL-1b-induced neurotoxicity in the substantia
nigra in these animals. Interestingly, active infection
with the Gram-positive bacterium Streptococcus pneumoniae did not exacerbate features of disease in a
number of disease models: Tg2576 AD model, the
Thy1-A30P-a-SYN PD model, and the G93A SOD-1
ALS model (Ebert et al., 2010). Although those studies
are partially confounded by the administration of antibiotics to infected animals within 24 h of infection, it
is possible that Gram-positive bacteria, which lack
LPS, constitute a less significant stimulus to the diseased brain. Deleterious effects have, however, been
observed with other stimuli. The acute and longitudinal exacerbation of chronic neurodegenerative disease
has been demonstrated after systemic challenge with
the double-stranded RNA poly I:C (Field et al., 2010).
These animals showed exaggerated CNS IL-1b and
also Type I interferon (IFN a/b) responses to this
mimic of systemic viral infection. Among the specific
Type I interferon-responsive genes robustly elevated
was RNA-dependent protein kinase (PKR). Increased
activity of this kinase has been shown both to induce
79
apoptosis (Balachandran et al., 1998) and to induce
changes in eIF2a, which impairs LTP and memory
consolidation (Jiang et al., 2010). The data arising
from this poly I:C study suggest that one might think
of disease progression as a consequence of the cumulative effects of multiple systemic insults (as opposed to
one long-term peripheral inflammatory condition): poly
I:C was administered three times, two weeks apart,
with each successive challenge producing acute onset
deficits that were progressively more severe and less
reversible as the challenges were superimposed on disease at more progressed stages (Field et al., 2010)
(Fig. 3). This mimics the fluctuating and variable rate
of decline seen in Alzheimer’s disease patients (Holmes
and Lovestone, 2003). Consistent with the idea that
systemic viral infection may contribute to neurodegenerative disease, there is evidence that the H5N1
influenza virus can be disseminated and even enter
the CNS and induce inflammation and neurodegenerative features such as a-synuclein aggregation and nigral neuronal loss (Jang et al., 2009), and indeed there
is evidence for increased incidence of PD in the wake
of an influenza epidemic, causing significant encephalitis, in the early 20th century (Ravenholt and Foege,
1982).
Using another model of Parkinson’s disease, induced
by intranigral injection of 2 lg LPS, ulcerative colitis
(induced by 5% sodium dextran sulphate; DSS) was also
shown to significantly exacerbate dopaminergic neuronal
loss (Villaran et al., 2010). DSS induced significant systemic levels of IL-1b and increased CNS expression of
iNOS, TNF-a and ICAM-1 in the PD mice. There was
also some evidence of blood brain barrier (BBB) breakdown, but interpretation of these data is complicated by
the injection of LPS into the nigra during the period of
ulcerative colitis. Thus the model examines the severity
of LPS-induced nigral degeneration when performed in
the presence of significant peripheral inflammation.
One recent study assessed the impact of osteoarthritis,
a progressive disease associated with aging, on AD pathology in the APP/PS1 double transgenic model. Since
IL-1b is known to contribute to osteoarthritis pathology,
the Col1-IL1bXAT Cre inducible model was used to model
osteoarthritis and when these animals were crossed
with APP/PS1 mice and injected with Cre to induce IL1b expression, there were significant exacerbations of Ab
deposition and associated microglial activation (Kyrkanides et al., 2011). Atherosclerosis also constitutes a systemic inflammatory disease, and is obviously very prevalent in western societies. Atherosclerosis is a major risk
factor for stroke and recent studies show that the susceptible ApoE2/2 mice, when fed on fat-rich diets such as
the Paigen diet (Paigen et al., 1985), develop atherosclerotic plaques but also develop evidence of cerebrovascular
and microglial activation (Drake et al., 2011). Whether
this state predisposes these microglia to respond more
robustly to LPS has not been examined, but there is evidence that stroke outcomes are more severe in these animals (Horsburgh et al., 2000). Systemic inflammation
induced by LPS also exacerbates stroke outcomes, but in
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Fig. 3. Systemic inflammation induces acute neuronal dysfunction
and contributes to accumulating pathological burden. Top panel: This
schematic depicts how a range of inflammatory molecules can induce
acute neuronal dysfunction directly via neuronal receptors for many of
these mediators. However, many of the same molecules can also contribute to damage and death of neurons. Thus the same insult may produce recoverable dysfunction as well as cell damage and death. It is
also conceivable that certain inflammation-induced mediators may be
involved only in acute dysfunction while others directly contribute to
pathology. Bottom panel: Progressive disease increases the risk and severity of inflammation-induced functional decline. Successive inflammatory insults have progressively bigger effects on functional decline as
disease progresses. In this example three identical inflammatory challenges produce acute dysfunction that is initially minor and reversible,
but on subsequent insults the deficits are more severe and the recovery
does not reach the previous baseline. These experimental data mimic
the fluctuating course seen in demented patients and provide a clear
hypothesis for how multiple acute systemic insults contribute to progression of disease. The data are particularly relevant for the occurrence of delirium during dementia. (Data adapted from Field et al.,
Brain Behav and Immun, 24, 996-1007, ' (2010), with permission from
Elsevier).
GLIA
this case the mechanism appears to depend on LPSinduced systemic IL-1b and chemokine expression and
mobilization of neutrophils, and may be independent of
microglial activation (McColl et al., 2007). In a model of
liver injury, induced by bile duct ligation and resection,
animals with liver injury showed significant recruitment
of monocytes to the brain, dependent on peripheral TNFa signaling through TNFR1, to induce CNS MCP-1
(D’Mello et al., 2009). Though these findings showed that
this signaling pathway was important for induction of
sickness behavior rather than neurodegeneration, the
recruitment of monocytes to the brain by peripheral
organ disease has significant implications for chronic
neurodegenerative disease.
Given the now numerous reports of systemic inflammation’s impact on neurodegenerative pathology and
symptomology, it is worth considering the impact of
housing conditions on the inflammatory status in animal
models. SPF animals may show different susceptibility
to the effects of inflammation than conventionally
housed animals. Similarly, undetected infections in conventionally housed animals may contribute to variability
in makers of inflammation and pathology subsequently
observed. There are, unsurprisingly, few studies on this
subject, and apparently none that deal specifically with
neurodegenerative disease. There is evidence that animals housed in specific pathogen free (SPF) conditions
exhibited muted CNS inflammatory responses to administered adenovirus compared to those housed in conventional conditions (Ohmoto et al., 1999). Those mice previously exposed to adenovirus, peripherally, showed
CD81 T cell-skewed responses compared to the CD41 T
cell-dominated responses of naive mice. SPF mice also
showed more severe relapses in EAE compared with
conventionally housed animals (Birnbaum et al., 1998).
In the periphery it has been shown that a single challenge with zymosan could induce rheumatoid arthritis
in SKG mice under conventional conditions, but these
animals were not susceptible under SPF conditions
(Yoshitomi et al., 2005). It is of interest to know what
influence housing and environmental factors may have
had on the parameters of inflammation in animal models where systemic inflammatory stimuli were not deliberately applied.
Microglial-Mediated Mechanisms of Disease
Exacerbation
The primary effect of further activation of primed
microglia, after systemic LPS challenge, is an exaggerated proinflammatory response. This has been described
in prion disease, AD, PD, Wallerian degeneration, and
in aging. Some possible mechanisms whereby this
switch can effect degenerative changes have been
referred to, as they arose, in the above-mentioned sections. In this section, we discuss other possibilities for
systemic inflammation-induced exacerbation of disease
(Fig. 4).
SYSTEMIC INFLAMMATION AND CNS DISEASE
Classical proinflammatory mechanisms:
IL-1, TNF-a, and prostaglandins
The acute induction of IL-1b in the brain after systemic LPS challenges has been the hallmark of the previously primed microglial cell (Cunningham et al.,
2005b) and is induced by proinflammatory stimuli such
as LPS. IL-1 initiates cellular responses through its
interaction with IL-1RI to activate NF-jB, as well as
induction of mitogen-activated protein kinases (MAPK)
p38, extracellular related kinase (ERK)1/2, and c-jun Nterminal kinase (JNK) pathways (Parker et al., 2002).
Collectively these pathways are responsible for the
induction of several effector mechanisms discussed
below, including iNOS, COX, NADPH oxidase, and proteases including matrix metalloproteases and plasminogen activators. IL-1a has been much less studied, but
seems to be released from necrotic cells, and may be a
key step in the induction of postischemic inflammation,
albeit one that appears to contribute to neuronal damage (Boutin et al., 2001). However, it can also activate
the endothelium to facilitate peripheral leukocyte infiltration (Thornton et al., 2010) and may thus contribute
to damage arising from systemic inflammation. TNF-a is
also a robust inducer of NF-jB activation, but is more
widely implicated in cell death processes than most cytokines since direct engagement of the TNFRI p55 can be
sufficient to induce apoptosis. The TNF p55 receptor
forms a complex containing TNF receptor associated
death domain (TRADD), which can dissociate and
recruit FADD (FAS-associated via death domain) and
caspase-8 to initiate apoptosis (Micheau and Tschopp,
2003). The balance between death domain-initiated and
NFjB-initiated pathways is crucial in determining the
apoptotic potential of TNF-a signaling (Beg and Baltimore, 1996). However, there are now a very large number of studies suggesting that inhibition of TNF-a has
beneficial effects in animal models of disease and thus,
its acute up-regulation by systemic inflammatory events
is likely to have a significant impact on existing brain
pathology whether via direct apoptotic effects or by the
up-regulation of effector enzymes such as iNOS and
proteases.
The protective effects of NSAIDs on the development
of AD and PD obviously suggest that prostaglandins
generated from COX may be an important feature in
these diseases. COX-2 has often been the pharmacological target of choice against neuroinflammation since it is
induced by inflammatory stimuli (Cao et al., 1996; Ek
et al., 2001) but the evidence for increased expression in
chronic neurodegenerative diseases, including AD (Hoozemans et al., 2001; Yermakova et al., 1999), prion disease (Deininger et al., 2003), and HIV dementia (Griffin
et al., 1994) is actually stronger for COX-1. It is clear
that microglia can express both COX-1 and COX-2,
although there appears to be some debate about the latter. However, the involvement of different COX isoforms
(1 and 2), different specific synthases responsible for E,
D, I, and F prostaglandins and different receptors for
each of these prostaglandin classes have not received as
81
much attention as one might expect given the protective
effects of NSAIDs in AD and PD (see Cunningham and
Skelly, 2012 for review). There are studies suggesting
that microglial EP2 contributes to amyloid load and oxidative damage in the APP/PS1 model (Liang et al.,
2005), and consistent with the idea of both beneficial
and deleterious roles of microglia there is evidence that
deletion of the EP2 receptor improves microglial phagocytosis and decreases neurotoxicity (Shie et al., 2005).
Conversely, EP4 has recently been described to have an
anti-inflammatory role, limiting proinflammatory cytokine synthesis induced by LPS (Shi et al., 2010). While
it is known that some NSAIDs can lower Ab aggregation
independent of their anti-inflammatory activity (Weggen
et al., 2001), it has also been shown, in a large group of
pooled prospective studies, that ‘‘amyloid-lowering’’
NSAIDs are not more effective in reducing the risk of
AD than nonamyloid-lowering NSAIDs (Szekely et al.,
2008). Since systemic inflammation clearly increases
CNS prostaglandin concentrations with consequent
effects on behavior and cognition (Hein et al., 2007; Teeling et al., 2010) the characterization of the actions of
these molecules continues to be important.
Acute exacerbation of function: Delirium,
depression, and cognitive impairment
It is now clear that systemic inflammation can induce
acute working memory changes in aged animals (Chen et
al., 2008) and those with prior neurodegenerative disease
(Murray et al., 2012) or cholinergic neuronal loss (Field et
al., 2012). These cognitive changes are comparable to the
cognitive deficits observed in episodes of delirium in the
elderly and demented according to DSM-IV and ICD-10
descriptions (American Psychiatry Association, 1994;
WHO, 1992) and microglial priming as observed in these
model systems has gained acceptance as a contributor to
this clinical scenario (van Gool et al., 2010). Likewise both
infection (Barrientos et al., 2006) and surgery (Cibelli et
al., 2010) can impair the ability to form new contextual
memories and this is especially true in the aged, in which
microglia have been primed. Mechanisms for these acute
deficits are not yet clear, but it appears that IL-1b, TNFa, and PGE2, perhaps via direct effects on ACh or other
neurotransmitters, are involved. At least in the case of
IL-1, central administration of IL-1ra has been found to
be protective (Chapman et al., 2010; Cibelli et al., 2010).
IL-1b expression has been shown to impact on ACh outflow and to impair memory function (Taepavarapruk and
Song, 2010) and the impact of systemic LPS on working
memory deficits in those with prior cholinergic neuronal
loss can be protected against using the acetylcholinersterase inhibitor donepezil (Field et al., 2012). Understanding
mechanisms of delirium will prove very important in dementia since these episodes are now known to significantly affect long-term cognitive function (MacLullich et
al., 2009), to accelerate dementia (Fong et al., 2009) and
to shorten the time to permanent institutionalization
and death (Witlox et al., 2010). Priming of the microGLIA
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Fig. 4. Possible mechanisms of systemic inflammation-induced damage. Systemic inflammatory episodes (SIE) induce a plethora of inflammatory mediators that circulate in the blood. The levels of these mediators are dictated by the severity of the insult. In severe sepsis there is
both leakage of serum proteins into the brain and the additional complication of thrombosis and resulting brain hypoxia and hypoglycaemia,
which may result in neuronal death without microglial involvement.
BBB permeability is also affected by LPS/cytokines and in many disease states BBB integrity is already somewhat compromised. Even
with maintained integrity of the BBB, molecules shown in the lumen of
the blood vessel can induce the synthesis of most of these mediators on
the abluminal side, thus secreting these mediators into the brain parenchyma. Before SIE, microglia may be quiescent in most individuals,
but may be primed where there is prior CNS disease and/or where
there are genetic factors that make microglia more reactive (Nurr 1, for
example). Systemic inflammatory stimulation will induce phenotypic
switching of primed microglia and this will occur specifically in areas of
prior pathology. In each of the three cases shown, CNS microglia can
potentially make a large repertoire of damaging molecules, whether
they were making these before SIE or not. This list is not exhaustive
and there is no implication that the uppermost list only occurs in
severe sepsis or that the lower only occurs with prior disease. Given
that there has been little characterization of responses in repeated LPS
challenge studies, we have little idea of the evolution of the CNS
inflammatory profile after repeated challenges: these may be sensitized
or show tolerance. SIE, systemic inflammatory event; LPS, lipopolysaccharide; IL-1b, interleukin 1b; TNF-a, tumor necrosis-a; IgG, immunoglobulins; PGs, prostaglandins; BBB, blood brain barrier; NOX,
NADPH oxidase; iNOS, inducible nitric oxide synthase; ONOO2, peroxynitrite anion; IFN-a/b, Type I interferons a and b; MMPs; matrix metalloproteases.
glial population in aged rodents also appears to predispose these animals to exaggerated and prolonged features of depression (Godbout et al., 2008). These are
important complications that can occur frequently during the course of chronic neurodegenerative disease
and further dissection of mechanisms could offer significant benefits to patients. It is important to consider
the possibility that the same molecules may be
involved in acute, but recoverable, neuronal dysfunction, and in neuronal death leading to permanent loss
of function. Equally, reversible and irreversible neuronal dysfunction/damage may occur by distinct pathways (Figs. 3 and 4).
tion of multiple enzymes/complexes including the
NADPH oxidase, iNOS, and sometimes myeloperoxidase
(MPO). These enzymes/complexes form superoxide
(O22), nitric oxide (NO), and hypochlorous acid (HOCl),
respectively. Each of these enzymes have been described
in both PD patients and models and preclinical studies
have described a role for all three in toxicity to TH-positive cells of the substantia nigra (Choi et al., 2005;
Hunot et al., 1996; Wu et al., 2002). The peroxynitrite
anion ONOO2 is particularly toxic to neurons. Among
the most frequently cited proinflammatory and damaging aspects of microglial activation is the formation of
iNOS. The induction of transcription of this NF-jB-regulated gene is extremely common in studies of neuroinflammation and the expression of iNOS protein and the
synthesis of NO is a hallmark of the further activation
of primed macrophages (Johnson et al., 1983) and microglia (Cunningham et al., 2005b). It is striking that elevation of iNOS is most frequently observed in animal
models of PD, most of which employ either acute neuro-
Reactive oxygen and nitrogen species: iNOS and
NADPH oxidase
Microglia are capable, if sufficiently activated, of generating an oxidative burst involving the regulated inducGLIA
SYSTEMIC INFLAMMATION AND CNS DISEASE
toxins (MPTP, 6-OHDA) or rather severe LPS treatment
regimes: LPS i.c. (Herrera et al., 2000), or i.p. at 5 mg/
kg (Qin et al., 2007). However, despite reservations
about the acute and severe nature of the initial stimulus
in these studies, LPS has proved to induce apparently
self-sustaining inflammation (Qin et al., 2007), and
MPTP-induced inflammation has proved to have similar
longevity in monkeys and in humans (Langston et al.,
1999). Where robust iNOS induction has occurred after
systemic inflammation, induced by LPS or adenovirallyinduced IL-1b, inhibition (Pott-Godoy et al., 2008) or
deletion (Weberpals et al., 2009) of iNOS has been sufficient to protect nigral or other affected neuronal populations.
Phagocytosis: Axon pathology, cell death,
and protein aggregates
The degeneration of axons is something that is likely
to happen in almost all brain pathologies including
axon transection, stroke, and multiple progressive neurodegenerative diseases. Studies of Wallerian degeneration (Palin et al., 2008) showed that microglial cytokine
profiles were muted after acute optic nerve crush, but
the cells remain primed 28 days later and responded to
systemic LPS with phenotype switching to a more IL1b dominated profile and enhanced phagocytosis of
neuronal debris. While this phagocytosis would appear
to be beneficial in the context of successful clearance of
myelin and axonal debris from functionally dead neurons, there is in vitro evidence that stimulating phagocytosis can result in clearance of neurons that would
not otherwise have been committed to cell death: LPS
or lipotechoic acid treatment of neuronal and microglial
co-cultures, induced reversible neuronal display of
phosphatidyl serine (PS), via ROS/RONS production.
Mfge8 and the vitronectin receptor collaborate to facilitate microglial recognition of PS-positive cells and
effect uptake of the cell. However, multiple blocking
experiments suggest that many of these cells would
have survived had they not been phagocytosed (Neher
et al., 2011). There is recent evidence that systemic
LPS-induced activation or reactivation of lesions in the
EAE model of multiple sclerosis can lead to relapse
and to new iNOS expression and axonal transection, as
measured by APP end-bulbs (Moreno et al., 2011).
These studies revealed significant heterogeneity of different lesions in the EAE brain, but significantly the
authors showed increased microglial/macrophage iNOS
consistently co-localized with APP, and those lesions
that were iNOS negative were typically also APP negative and showed IL-10 and TGFb1 expression persisting for several days post-LPS, consistent with the
switching of some lesions to an M1 phenotype, but
maintenance of others in an M2 phenotype. Though
the EAE model has both innate and adaptive components, exacerbation of axonal pathology occurred significantly earlier than increased T-cell infiltration (Moreno
et al., 2011). These studies provide clear evidence that
83
brain lesions may lie relatively silent but later be reactivated by remote inflammatory stimuli and further
activation of primed microglia in this scenario is clearly
detrimental. In further EAE models, using fMOG or
the delayed type hypersensitivity to BCG (DTH) model,
LPS reactivated EAE lesions, resulting in increased demyelination and BBB breakdown (Serres et al., 2009).
The degree to which primed microglia contributed to
these effects is not clear, although macrophages were
clearly recruited from the periphery. Consistent with
the idea that complement activation can prime microglia, C3b-coated nerve fibers were found in close proximity to primed, IL-1b negative, microglia in MS brain,
and EAE progresses more slowly in Crry2/2 mice, in
the absence of priming (Ramaglia et al., 2012). Since
microglia are more abundant in white than in grey
matter in the human brain and are increased in number in the aged brain, systemic insults may have significant effects on major axonal tracts in the brain and
might be particularly disabling when reactivating white
matter microglia.
Conversely, there is evidence that further stimulation
of microglia in the AD transgenic brain, using intracerebral LPS, can enhance clearance of Ab (DiCarlo et al.,
2001; Herber et al., 2004). While Ab clearance was
improved, there was insufficient assessment of cellular
infiltration in those studies to rule out a significant contribution of infiltrating monocytes and neutrophils,
which surely would occur upon stimulation with LPS at
the high doses used (4 and 10 lg LPS i.c.). We have performed similar experiments in the ME7 model of prion
disease and, with just 0.5 lg LPS, found dramatic exacerbation of inflammation, marked neutrophil infiltration
but surprisingly unaltered levels of extracellular PrPSc,
the prion disease-associated amyloid species (Hughes
et al., 2010). Consistent with this, there is evidence that
phagocytic activity and proinflammatory cytokine
synthesis are inversely related in macrophages and
microglia (Fadok et al., 1998; De Simone et al., 2002;
Takahashi et al., 2005), which is at variance with the
prior proposal that more phagocytic microglia are also
more pro-inflammatory (Streit et al., 1999).
Complement, Fc Receptors, IgG, and BBB
breakdown
Experiments demonstrating the markedly up-regulated expression of activating Fcg receptors FcgRII,
FcgRIII, and FcgRIV upon systemic LPS challenge to
ME7 animals (Lunnon et al., 2011) suggest other possibilities for neurodegeneration. Fc receptors bind IgG,
and the same study shows evidence of BBB breakdown,
leakage of IgG into the brain, and co-localization of IgG
with CD68-positive microglia. Association between IgG
and Fc receptors is described, in immune cells and in
microglia (Ulvestad et al., 1994a), to promote phagocytosis, oxidative burst, and antibody-dependent cytotoxicity
(see Okun et al., 2010, for review). A study of direct
injection of IgG purified from Parkinson’s disease
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CUNNINGHAM
patients into the substantia nigra of wild-type and
FcgR2/2 mice showed TH-positive neuronal death in
the nigra only in animals carrying the FcgR (He et al.,
2002). Increased expression of these Fc receptors has
also been observed in both AD (Peress et al., 1993) and
MS (Ulvestad et al., 1994b) brains.
The presence of increased IgG in the diseased brain
may also be a trigger for complement activation, but
there is also evidence for activation of complement
even in the absence of IgG, via C1q binding to Ab
(Rogers et al., 1992). The full activation of complement
pathways will eventually lead to formation of the C5b9 membrane attach complex (MAC) that can induce
bystander cell lysis. It is of interest that postmortem
AD brains contain evidence for the C5b-9 membrane
attack complex, while APP transgenic mice do not
(McGeer and McGeer, 2002; Reichwald et al., 2009),
perhaps arguing for a role for secondary inflammatory
stimulation to complete assembly of the MAC, as is
observed at postmortem.
The discussion of IgG-mediated effects cannot be easily separated from the topic of BBB breakdown.
Impaired BBB function with ageing has been shown in
rodents and a meta-analysis of BBB function with ageing in humans showed that BBB permeability increased
with ageing and was further increased in patients with
vascular or Alzheimer’s dementia (Farrall and Wardlaw,
2009). In normal animals, LPS shows surprisingly little
evidence of penetration of the brain (Banks and Robinson, 2010; Singh and Jiang, 2004), although at high
doses it can induce robust BBB breakdown (Wispelwey
et al., 1988). Recent intravital microscopy studies have
shown increased extravasation of 70,000 MW dextran in
real time after challenge with 1 mg/kg LPS (Ruiz-Valdepenas et al., 2011). Thus, even if LPS itself has limited
access to the brain parenchyma, it is certainly plausible
that there will be significant leakage of plasma proteins
across the BBB in the sorts of regimes used in many of
the studies cited above. Of course, in cases where underlying disease increases access of molecules to the brain
parenchyma, via BBB breakdown, LPS might directly
activate brain cells.
Apart from LPS and IgG, Increased BBB permeability also allows access of other microglial activating
molecules to the brain. Thrombin is known to enter
the brain during BBB breakdown, has been shown to
activate microglia via the PAR-1 receptor (Suo et al.,
2002) and, when injected into the substantia nigra,
can result in nigral neuronal death (Carreno-Muller
et al., 2003). Likewise fibrinogen and albumin ‘‘leak’’
into the CNS when the BBB is breached (Nishioku
et al., 2009) and can activate proinflammatory and
neurotoxic pathways in microglia (Hooper et al., 2005;
Piers et al., 2011).
For all that has been said about microglia thus far,
the distinction between expression of proinflammatory
cytokines by the endothelium, the perivascular macrophages, and microglia or indeed astrocytes has not often
been documented in the cited studies of systemic inflammatory activation. It is clear that multiple routes exist
GLIA
to convert a peripheral inflammatory signal into a CNS
equivalent: activation of the cerebral endothelium, of the
circumventricular organs, of the perivascular macrophages as well as transport of cytokines across the BBB
and stimulation of vagal afferents arising in the viscera
have all been well described after systemic inflammation
and are discussed elsewhere (Banks and Erickson, 2010;
Konsman et al., 2002). While each of these routes is capable of transmitting a signal it is likely that there is
some redundancy in these routes. We have recently
found that blocking systemic cytokines using dexamethasone was insufficient to block CNS inflammatory cytokine synthesis, and that LPS was detectable in the blood
even at a dose of 100 lg/kg (Murray et al., 2011). This
means that in all of the ‘‘repeated LPS challenge’’ studies cited above, the brain endothelium will have been
exposed to LPS irrespective of what systemic inflammatory mediators were also induced. Obviously in those
studies where LPS dosing is sufficient to induce BBB
breakdown, the brain parenchyma itself will be exposed
to LPS. Similarly, it is well established that prostaglandins have an important role in transducing systemic
inflammatory signals into the CNS (Cao et al., 1996; Ek
et al., 2001), and since these are effectively targeted by
NSAIDs, it is plausible that NSAID protection against
the development of AD and PD may work in part by preventing the deleterious CNS consequences of systemic
inflammatory activation.
Boosting immune responses to treat disease
It has been suggested (Yong and Rivest, 2009) that
boosting the immune response could be a beneficial
strategy in neurodegenerative disease. This hypothesis
is based on the idea that the microglial cell has both
beneficial and deleterious roles in degenerative disease
and that promotion of the beneficial and suppression of
the deleterious could, for example, boost phagocytosis of
plaque material without significantly disrupting neuronal integrity. While there is some preclinical data to
support this, the only clinical data that can currently
address this possibility are vaccination studies in AD,
which have not successfully replicated (Holmes et al.,
2008; Salloway et al., 2009) their resounding success in
preclinical laboratories (Schenk et al., 1999). There has
been strong evidence that vaccination against Ab can
clear amyloid, but this has not slowed disease progression (Holmes et al., 2008) and has lead to some significant adverse events (Nicoll et al., 2003). One possible
reason for this may be the increased expression of Fc
receptors occurring during chronic neurodegeneration
(Lunnon et al., 2011; Peress et al., 1993). It is also proposed that infiltration of the brain by bone marrow
derived myeloid cells can have beneficial effects on the
diseased brain (Simard et al., 2006). Indeed frequent
injections of the TLR9 ligand CpG can reduce amyloid
pathology and improve working memory deficits in the
Tg2576 model of AD (Scholtzova et al., 2009) suggesting
that the systemic inflammatory mediator profile may be
SYSTEMIC INFLAMMATION AND CNS DISEASE
a key determinant of the CNS outcomes of these systemic challenges. Unfortunately these authors did not
report the systemic and CNS inflammatory profile after
this repeated CpG regime. Irrespective of these data,
the possibility of beneficial effects have to be examined
against the consistent clinical observation that patients
who experience systemic infections or inflammation arising from surgery or injury do not fare well: they frequently suffer episodes of delirium, and these episodes
typically lead to accelerated cognitive and functional
decline (Witlox et al., 2010). Thus, while boosting
aspects of systemic inflammation could theoretically be
beneficial, this is a complex question and one that simply requires robust testing in multiple relevant models.
Current evidence from patients suggests that generalized systemic inflammation is almost universally deleterious. The clinical evidence for disease exacerbation is
discussed below.
Clinical Evidence: Systemic Inflammation
Negatively Influences Disease
Much has been made of inflammation as a double
edged sword, but with regard to systemic inflammation,
one thing seems relatively clear: when elderly individuals and patients with neurodegenerative disease experience systemic inflammatory episodes, such as infections,
they typically do not show improvements of their condition: there is now good evidence that they get worse.
One very clear example of this is delirium. It is now
clear that dementia is the biggest risk factor for delirium and systemic inflammation is one the most frequent
triggers and there is a strong association between episodes of delirium and subsequent cognitive decline,
acceleration of dementia progression and shorter time to
permanent institutionalization and death. Thus it is difficult to argue for anything other than deleterious
effects of systemic inflammation in these patients.
Indeed there are multiple clinical studies that indicate
negative outcomes for patients after systemic inflammation. While several studies have examined the association of specific infectious agents with Alzheimer’s
disease, including HSV-1, Chlamydia pneumonia and
spirochetes (see Holmes and Cotterell, 2009, for review)
observations have not been consistent. However, two or
more infections, of any type, over a 4-year period
increased the risk of AD by twofold in a general practitioner database review (Dunn et al., 2005) and general
ill health was significantly associated with cognitive
decline in two further studies (Strandberg et al., 2004;
Tilvis et al., 2004). MMSE scores were shown to
decrease with increasing viral burden and Herpes simplex virus and cytomegalovirus were of particularly high
risk (Strandberg et al., 2003) although these pathogens
have not been specifically implicated elsewhere. These
data recall evidence of a major influenza epidemic in the
early 20th century, which caused encephalitis and subsequently increased parkinsonism (Ravenholt and Foege,
1982), but without robust evidence of viral antigens
85
inside the CNS (Lo et al., 2003). In the absence of an
ongoing association between particular infections and
risk of disease, it seems reasonable to assume that the
robust systemic acute phase response or Ôcytokine stormÕ
occurring during acute disease may affect the brain in
similar ways for a large number of different infections.
Periodontitis, a gum infection that is very common the
community, caused most often by infection with the
Gram-negative Porphyromonas gingivalis, has now been
shown to be a significant risk factor for Alzheimer’s disease (Kamer et al., 2009). In addition to these association studies, it has been shown that treating infection
and vaccination against a number of common diseases
can reduce the risk of development of Alzheimer’s disease (Verreault et al., 2001) and antibiotic treatment of
mild to moderate AD patients with doxycycline and
rifampin can slow cognitive decline even in established
disease (Loeb et al., 2004). While most of the above studies examined the possibility of infections as etiological
factors, the hypothesis that acute systemic inflammation, superimposed on established disease, would exacerbate or accelerate disease was examined in a group of 85
AD patients. Though only a small fraction of these
patients showed elevated serum IL-1b, this was significantly associated with increased cognitive decline across
a 2-month period (Holmes et al., 2003). Further studies,
in a cohort of 275 AD patients across 6 months, showed
that elevated serum TNF-a was significantly correlated
with accelerated cognitive decline and those patients
with low serum TNF-a showed stable cognitive function
across this period. While those with elevated serum
TNF-a or with carer-reported infection showed greater
decline, those with both of these features showed considerably greater decline (Holmes et al., 2009). All AD
patients reaching criteria for delirium were omitted
from this study, so one can say that even in the absence
of delirium, these systemic inflammatory events are
associated with increased pathological burden. It is of
note that not all patients with elevated serum TNF-a
suffered acute systemic inflammatory events and this
TNF-a may arise from a number of other chronic comorbidities such as obesity, atherosclerosis, diabetes and
smoking, all of which have a systemic inflammatory
component (Drake et al., 2011; Yaffe et al., 2004). As discussed above, there are now a number of preclinical
studies demonstrating exacerbation of CNS inflammation/function resulting from inflammatory liver damage
(D’Mello et al., 2009), osteoarthritis (Kyrkanides et al.,
2011), atherosclerosis (Drake et al., 2011), and diabetes
(McClean et al., 2011). While it is now relatively clear
that patients suffering episodes of delirium show longterm cognitive impairments, even patients with altered
mental status not fulfilling criteria for delirium (often
classified as subsyndromal delirium) show evidence of
long term cognitive impairment in geriatric (Cole et al.,
2003) and critical care settings (Jones et al., 2006).
Thus, acute systemic inflammatory episodes have a negative impact on CNS function, induce neuropathological
changes and appear to accelerate neurodegenerative disease. The presence of chronic peripheral inflammatory
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CUNNINGHAM
disease may have even worse prognosis for the degenerating brain. The recent findings that systemic anti-TNFa treatment for rheumatoid arthritis (Chou, 2010) is
protective against AD brings full circle, the original findings that NSAIDs taken for RA were also protective
against the development of AD.
CONCLUSION
It is clear that severe systemic inflammatory episodes
such as severe sepsis induce considerable CNS pathology
and disability. Multiple preclinical studies have shown
that robust and repeated systemic inflammatory activation can also produce neurodegeneration. These degenerative changes are particularly marked when animals
have some underlying genetic predispostion or have
existing degenerative pathology and/or primed microglia.
Moreover, recent work in ageing shows that simply
being exposed to an ageing bloodstream is enough to
have significant impacts on neurogenesis and learning
and memory (Villeda et al., 2011), with chemokines
appearing to play a key role in this decline. There
remains much to learn about the role of microglia and
indeed the cerebrovascular endothelium and astrocytes
in this periphery to brain communication, not to mention roles for infiltrating cells during inflammatory stimulation. It is reasonable to assume that this communication may be more complex than meets the eye and it
will be important, in the coming years, to try to mimic
both disease-associated inflammation and disease-exacerbating systemic inflammation in a proportionate fashion if we are to avoid making conclusions that are too
simplistic and that will not translate to the human population. These investigations have considerable implications for our interpretation and further development of
trials with anti-inflammatory drugs. Thus far, NSAIDs
have provided protection when taken for many years
but have been unable to treat established disease. This
is consistent with the idea that a lifetime of peripheral
inflammatory events contributes to brain pathology. One
very promising aspect of the unmasking of systemic
inflammation as a significant contributor to CNS disease
is that if we can successfully identify key pathways to
dysfunction, it may be possible to treat CNS disease
with drugs that do not require access to the brain parenchyma.
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