Systemic Inflammation and the Brain: Novel Roles of Genetic, Molecular, and Environmental Cues as Drivers of Neurodegeneration

Abstract

The nervous and immune systems have evolved in parallel from the early bilaterians, in which innate immunity and a central nervous system (CNS) coexisted for the first time, to jawed vertebrates and the appearance of adaptive immunity. The CNS feeds from, and integrates efferent signals in response to, somatic and autonomic sensory information. The CNS receives input also from the periphery about inflammation and infection. Cytokines, chemokines, and damage-associated soluble mediators of systemic inflammation can also gain access to the CNS via blood flow. In response to systemic inflammation, those soluble mediators can access directly through the circumventricular organs, as well as open the blood-brain barrier. The resulting translocation of inflammatory mediators can interfere with neuronal and glial well-being, leading to a break of balance in brain homeostasis. This in turn results in cognitive and behavioral manifestations commonly present during acute infections - including anorexia, malaise, depression, and decreased physical activity - collectively known as the sickness behavior (SB). While SB manifestations are transient and self-limited, under states of persistent systemic inflammatory response the cognitive and behavioral changes can become permanent. For example, cognitive decline is almost universal in sepsis survivors, and a common finding in patients with systemic lupus erythematosus. Here, we review recent genetic evidence suggesting an association between neurodegenerative disorders and persistent immune activation; clinical and experimental evidence indicating previously unidentified immune-mediated pathways of neurodegeneration; and novel immunomodulatory targets and their potential relevance for neurodegenerative disorders.

Full text

CELLULAR NEUROSCIENCE
REVIEW ARTICLE
published: 02 February 2015
doi: 10.3389/fncel.2015.00028
Systemic inflammation and the brain: novel roles of
genetic, molecular, and environmental cues as drivers of
neurodegeneration
Roman Sankowski 1,2*†, Simone Mader 2*†and Sergio IvánValdés-Ferrer1,2,3*†
1Elmezzi Graduate School of Molecular Medicine, Manhasset, NY, USA
2Feinstein Institute for Medical Research, Manhasset, NY, USA
3Department of Neurology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, Mexico
Edited by:
Victoria Campos, Instituto Nacional de
Neurologia y Neurocirugia, Mexico
Reviewed by:
Rafael Linden, Federal University of
Rio de Janeiro, Brazil
Muzamil Ahmad, Indian Institute of
Integrative Medicine, India
Claudia Verderio, Istituto di
Neuroscienze, Italy
*Correspondence:
Roman Sankowski, Simone Mader,
and Sergio Iván Valdés-Ferrer,
Feinstein Institute for Medical
Research, 350 Community Dr.,
Manhasset, NY 11030, USA
e-mail: rsankowski@nshs.edu;
smader@nshs.edu; svaldesfer@
nshs.edu, sivaldes@gmail.com
†Roman Sankowski, Simone Mader
and Sergio Iván Valdés-Ferrer have
contributed equally to this work.
The nervous and immune systems have evolved in parallel from the early bilaterians, in
which innate immunity and a central nervous system (CNS) coexisted for the first time,
to jawed vertebrates and the appearance of adaptive immunity. The CNS feeds from,
and integrates efferent signals in response to, somatic and autonomic sensory informa-
tion. The CNS receives input also from the periphery about inflammation and infection.
Cytokines, chemokines, and damage-associated soluble mediators of systemic inflamma-
tion can also gain access to the CNS via blood flow. In response to systemic inflammation,
those soluble mediators can access directly through the circumventricular organs, as well
as open the blood–brain barrier. The resulting translocation of inflammatory mediators can
interfere with neuronal and glial well-being, leading to a break of balance in brain home-
ostasis. This in turn results in cognitive and behavioral manifestations commonly present
during acute infections – including anorexia, malaise, depression, and decreased physical
activity – collectively known as the sickness behavior (SB). While SB manifestations are
transient and self-limited, under states of persistent systemic inflammatory response the
cognitive and behavioral changes can become permanent. For example, cognitive decline
is almost universal in sepsis survivors, and a common finding in patients with systemic
lupus erythematosus. Here, we review recent genetic evidence suggesting an associa-
tion between neurodegenerative disorders and persistent immune activation; clinical and
experimental evidence indicating previously unidentified immune-mediated pathways of
neurodegeneration; and novel immunomodulatory targets and their potential relevance for
neurodegenerative disorders.
Keywords: neurodegeneration, systemic inflammation and sepsis, autoimmune disorders, anti-brain antibodies,
TNF, HMGB1, connectome
INTRODUCTION: AN EVOLUTIONARY PERSPECTIVE
All multicellular organisms have germ-line encoded surveillance
systems destined to detect potentially dangerous, perhaps lethal,
invaders (Medzhitov and Janeway, 1997). This extremely effective
response, the innate immunity, depends on detection of spe-
cific molecular patterns present in invaders, but not expressed
by self-tissues. Innate immunity aroused approximately 600 mil-
lion years ago, and is evolutionarily conserved across species and
kingdoms. The main components of innate immunity – from toll-
like receptors (TLR) to inflammasomes – are highly conserved
from plants to mammals (Jones and Dangl, 2006).Adaptive immu-
nity appeared much later in evolution, perhaps 500 million years
ago, and is only present in vertebrates (Cooper and Alder, 2006;
Moresco et al., 2011). Unlike innate immunity, adaptive immu-
nity depends on one individual’s experience, in which adaptive
responses form with high efficiency only against antigens that
have been recognized and presented by the innate immunity.
Although the origin of the nervous system remains controver-
sial, the first centralized nervous system probably appeared with
the first bilateral organisms (organisms with two relatively identi-
cal halves, called bilaterians ) during the Ediacaran period around
550 million years ago (Knoll et al., 2004). Ever since, both ner-
vous and immune systems have co-evolved and are in constant
communication.
The nervous system of the evolutionarily ancient nematode
Caenorhabditis elegans has the ability to regulate innate immune
responses (Andersson and Tracey, 2012), and aid in decision-
making regarding finding bacteria that can be used as food and
avoiding pathogenic bacteria (Reddy et al., 2009). In mammals, the
nervous system also has the ability to sense inflammatory stimuli
directly, thus allowing to recognize a potential source of dam-
age through generation of pain, and to modulate the response to
infection (Mina-Osorio et al., 2012;Chiu et al., 2013a). Although
the afferent pathways and integration of immune information in
the brain are areas of active research, there is evidence that cen-
tral muscarinic signaling modulates inflammation in experimental
sepsis (Pavlov et al., 2009;Rosas-Ballina et al., 2015), obesity (Sata-
pathy et al., 2011), and inflammatory colitis (Ji et al., 2014). The
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Sankowski et al. Systemic inflammation and neurodegeneration
efferent axis of neuroimmune control is better understood after
the cholinergic anti-inflammatory pathway (CAP) (Borovikova
et al., 2000), a cholinergic reflex system that regulates inflamma-
tion via the vagus nerve that stimulates the splenic nerve to release
noradrenaline. Noradrenaline in turn stimulates a subset of acetyl-
choline (ACh)-producing splenic T-cells (CD4+CD44hiCD62Llo )
to release ACh, which binds to α7 nichotinic receptors on the
surface of macrophages, resulting in down-regulation of TNF by
blocking the nuclear translocation of nuclear factor kappa B (NF-
κB) (Rosas-Ballina et al., 2011). Thus far, this is a unique scenario
in which an immune cell acts as interneuron in a reflex system.
Electrical as well as chemical stimulation of the CAP have been
shown to decrease the inflammatory burden and increase survival
of experimental sepsis (Borovikova et al., 2000;Bernik et al., 2002).
Neuroimmune modulation is a flexible phenomenon thatrelies
on environmental cues from a continuously changing milieu. Peo-
ple undergoing persistent stress have been found to display abnor-
mal immune responses. For instance, caregivers of Alzheimer
disease (AD) patients have higher levels of anxiety and depression
than age-matched controls; otherwise, these healthycaregivers also
have reduced total T-cells and T helper cells in peripheral circula-
tion, as well as higher titers of anti-Epstein–Barr virus antibodies
(Kiecolt-Glaser et al., 1987). Moreover,the observed immune and
behavioral changes are increased in proportion to disease progres-
sion. T-cell response to mitogenic stimuli progressively decreases,
and while all subjects have the same number of infectious episodes,
the number of days unable to perform activities of daily living,
as well as the number of doctor visits are significantly increased
in AD caregivers (Kiecolt-Glaser et al., 1991). One mechanism
for the immune dysfunction in response to chronic stress is a
reduction of telomeres and telomerase activity, potentially leading
to early immune senescence (Epel et al., 2004). Mice with natu-
rally elevated anxiety levels have increased activated microglia and
perivascular macrophages in the brain, than less anxious strains (Li
et al., 2014), suggesting that anxiety can increase the inflammatory
background in the brain.
The acute effects of systemic inflammation upon cognition and
behavior are not limited to the elderly or the critically ill. As we
have witnessed in ourselves and those near us, even a minor and
self-limited common cold induces a transient syndrome known as
sickness behavior (SB) marked by fatigue, depression,lack of drive,
malaise, sleep disturbances, decreased physical activity, and social
interactions, as well as cognitive impairment (Capuron et al., 1999,
2001). Healthy volunteers develop anxiety, depression, and mem-
ory impairment in response to a low dose of lipopolysaccharide
(LPS), and the development of such clinical scenario correlates
with TNF secretion (Reichenberg et al., 2001). Some chronic infec-
tions may go unrecognized for long periods, as is the case in
tuberculosis, human immunodeficiency virus (HIV), hepatitis B
virus (HVB), or hepatitis C virus (HCV). Unlike septic patients,
patients with chronic infections have an organized and targeted
immune response (versus a massive and diffuse one in sepsis),
even if the response is ineffective to clear the infection. Those
patients, however, have increased cognitive and behavioral prob-
lems. For instance, patients with HCV infection have increased
rates of fatigue and depression, as well as evidence of metabolic
brain dysfunction in the absence of acute hepatitis (Forton et al.,
2001, 2002;Hilsabeck et al., 2002). Patients with chronic HCV that
have been treated with pegylated interferon (IFN)-αdevelop sig-
nificantly higher incidence of depression when compared to the
patients’ state before IFN-αadministration (Reichenberg et al.,
2005). This supports the role of large loads of inflammatory
cytokines in inducing and sustaining brain dysfunction. Exper-
imentally, NADPH oxidative activity and nitric oxide synthase
(iNOS) are induced in the brain shortly after systemic inflam-
mation (Wong et al., 1996;Yokoo et al., 2012), potentially leading
to NMDA-dependent neurotoxicity (Dawson et al., 1993). Evi-
dence derived from post-mortem studies indicates that iNOS is
also induced in the brain of patients dying of severe sepsis, but the
role of iNOS as inductor of neurotoxicity in response to systemic
inflammation has not been assessed in patients surviving severe
sepsis (Sharshar et al., 2003). Experimentally, preemptive admin-
istration of the free radical scavenger endarvone before sepsis
induction resulted in reduced neuronal damage and blood–brain
barrier (BBB) permeability (Yokoo et al., 2012). Administration of
the antioxidants N-acetylcysteine and deferoxamine shortly after
murine sepsis induction has shown long-term neuroprotective
effects (Barichello et al., 2007).
IMMUNITY IN SEPSIS
The immune system is in a constant state of surveillance against
potential pathogens and self-generated molecules indicative of
damage. Under normal conditions, inflammation is a well-
orchestrated response with constant fine-tuning. Once microor-
ganisms have breached the skin and mucosal barriers, innate
immunity is critical in preventing further invasion by launch-
ing inflammation. After the infection source has been cleared,
the inflammatory response also plays an important role in tis-
sue repair and functional healing. When the source of damage
has been controlled, the same mechanisms that initiated and reg-
ulated inflammation will dampen the response. Large loads of
pathogens, or infection by highly virulent pathogens, can trigger
an en-masse systemic response that leads to sepsis and multiple
organ failure (Deutschman and Tracey, 2014). Moreover, dur-
ing sepsis the inflammatory response does not resolve for several
days or weeks (Valdés-Ferrer, 2014), leading to persistent release
of high-mobility group box-1 (HMGB1) (Valdés-Ferrer et al.,
2013b). HMGB1 is a highly conserved nuclear protein that can be
passively released by stressed cells, or actively secreted by mono-
cytes and other immune cells in response to inflammatory signals,
playing a critical role in the innate immune response to inflam-
matory and sterile injury alike (Andersson and Tracey, 2011).
HMGB1 in turn primes resident monocytes toward an inflamma-
tory, cytokine producing phenotype (Valdés-Ferrer et al., 2013a).
Severe trauma, as well as surgery can lead to large loads of endoge-
nous pro-inflammatory molecules (damage-associated molecular
patterns (DAMPs) being released. A few DAMPs have been shown
to induce brain dysfunction in vivo. Of those, TNF and IL-1 can
mediate long-standing cognitive and behavioral changes and, in
experimental settings, interfering with the effect of TNF reduces
the effect of trauma in the formation of contextual memory
(Terrando et al., 2010b). A number of genes regulating immune
responses are also closely related to neurodegenerative diseases
(Table 1).
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Sankowski et al. Systemic inflammation and neurodegeneration
Table 1 | Major immune genes associated with neurodegenerative diseases.
Gene/
protein
Disease (reference) Function Expressing cells Consequence of mutation
TREM2 AD (Guerreiro et al., 2013;Jonsson et al.,
2013), PD (Rayaprolu et al., 2013), FTD
(Rayaprolu et al., 2013), Nasu–Hakola
disease (Paloneva et al., 2002)
Anti-inflammatory, pro-phagocytic Myeloid cells Loss-of-function
(Kleinberger et al., 2014)
TYROBP AD (Zhang et al., 2013), Nasu–Hakola
disease (Paloneva et al., 2000)
Binding partner of TREM2 Immune cells Loss-of-function
CD33 AD (Paloneva et al., 2002;
Bertram et al., 2008)
Anti-inflammatory, anti-phagocytic
(Bradshaw et al., 2013;Griciuc
et al., 2013)
Myeloid cells Increased expression and
activation (Bradshaw et al.,
2013)
TREX 1 NPSLE (de Vries et al., 2010), SLE
(Lee-Kirsch et al., 2007b), AGS (Crow
et al., 2006), familial chilblain lupus
(Lee-Kirsch et al., 2007a)
Cytosolic DNA clearance (Stetson
et al., 2008)
Ubiquitous Loss-of-function
CSF1R HDLS (Rademakers et al., 2012) Microglial proliferation and
differentiation (Stanley et al., 1997)
Myeloid cells Loss-of-function
SOD1 fALS (Rosen, 1993) O2−scavenging Ubiquitous Loss-of-function (Ghadge
et al., 1997;Pasinelli et al.,
1998)
GRN Tau negative FTD (Baker et al., 2006) Secreted chemoattractant factor,
pro-phagocytic (Pickford et al.,
2011), anti-inflammatory
inflammation (Martens et al., 2012)
Widely expressed Loss-of-function
(Chen-Plotkin et al., 2010)
CR1 AD (Lambert et al., 2009) Pro-phagocytic Widely expressed Unknown, loss-of-function?
(Wyss-Coray et al., 2002)
HLA–DRB5 PD (International Parkinson Disease
Genomics Consortium et al., 2011),
AD (Yu et al., 2015)
Antigen presentation Antigen presenting cells,
inducible on other cell types
(Ting and Trowsdale, 2002)
Unknown, deregulation of
inflammatory response?
AD, Alzheimer’s disease; AGS, Aicardi–Goutières syndrome; CR1, complement receptor 1; fALS, familial amyotropic lateral sclerosis; FTD, frontotemporal dementia;
GRN, granulin gene; PD, Parkinson disease; NPSLE, neuropsychiatric SLE; HDLS, hereditary diffuse leukoencephalopathywith spheroids; SOD, super oxide dismutase;
TREM, triggering receptor expressed on myeloid cells;TYROBP,TYRO protein tyrosine kinase-binding protein.
CEREBRAL CONSEQUENCES OF SYSTEMIC INFLAMMATION:
WHAT WE HAVE LEARNED FROM SEPSIS AND OTHER
INFLAMMATORY CONDITIONS
The nervous system is particularly vulnerable to damage in
response to systemic inflammation. Inflammation-induced infil-
tration of immune cells and mediators into the brain leads to
profound structural and functional changes (Figure 1). As a con-
sequence, up to 81% of septic patients develop sepsis-associated
delirium (SAD) (Ely et al., 2001, 2004), with elderly patients being
at particularly high risk (McNicoll et al., 2003;Iwashyna et al.,
2012). In the elderly, severe sepsis is sufficient to trigger new cog-
nitive decline of sufficient importance as to profoundly interfere
with quality of life (Iwashyna et al., 2010). SAD is not only common
in septic patients but also is a reliable indicator of bad prognosis
(Eidelman et al., 1996). Six-month mortality among septic patients
is twice as high in patients who develop SAD at any point in time
during hospitalization (Ely et al., 2004). Altered mental status is
more common in septic patients with bacteremia than in those
with negative blood cultures (Eidelman et al., 1996). Magnetic
resonance imaging (MRI) in patients with septic shock has shown
that new white matter lesions are common (Sharshar et al., 2007).
Neonatal sepsis is also marked by abnormalities of the white matter
(66% of infants in one cohort), and white matter lesions correlate
to poorer mental and psychomotor development at 2 years (Shah
et al., 2008). The burden of white matter damage worsens with
duration of shock, indicating that sepsis interferes with brain con-
nectivity (Figure 2). Gray matter damage in response to sepsis is
far less clear. Imaging and post-mortem studies from patients, as
well as data derived from experimental models, indicate that gray
matter damage is the norm. In comparison to subjects dying of
other causes, brain histology from severe sepsis patients shows a
higher number of CD68+and major histocompatibility complex
(MHC)-class II microglia in the cerebral cortex and the white mat-
ter. Moreover, in septic brains ameboid-shaped activated microglia
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Sankowski et al. Systemic inflammation and neurodegeneration
FIGURE 1 | Brain milieu changes in response to systemic
inflammation. Under healthy conditions the main cell types present in
the brain are neurons, oligodendrocytes, astrocytes, and microglia.
Neurons connect to each other through long axonal processes with
synapses. Oligodendrocytes support axons with myelin sheaths.
Astrocytes interact with blood vessels to form the blood–brain barrier
and maintain neuronal synapses. Microglia form long processes that
surveillance the brain and phagocytose apoptotic cells and prune inactive
synapses without induction of inflammation. Under inflammatory
conditions several mechanisms lead to neurodegeneration. Peripheral
immune cells and inflammatory molecules traverse the blood–brain
barrier exerting direct and indirect neuronal cytoxicity. Oligodendroglial
myelin sheaths can be affected leading to axonal degeneration.
Astrocytosis leads to reduced blood–brain barrier and synaptic
maintenance. Microgliosis leads to a pro-inflammatory microglial
phenotype with reduced phagocytic and tissue maintenance functions.
can be found in gray and white matter alike (Lemstra et al., 2007).
An MRI study of premature infants showed reduced volume of
deep gray matter structures, and although the findings were con-
sistent in the small subset of septic infants, those were not different
from premature non-septic infants (Boardman et al., 2006).
In experimental sepsis, persistent cognitive impairment has
been observed in rats completely recovered and with negative
blood cultures. This indicates that clearing the trigger of sep-
sis does not prevent the appearance of persistent brain damage
(Barichello et al., 2005). Brain mitochondria become dysfunc-
tional during experimental sepsis, showing increased proton per-
meability, inadequate membrane potential recovery, and reduced
oxidative phosphorylation (d’Avila et al., 2008). In mice, the BBB
becomes leaky within 24 h following sepsis induction (Yokoo et al.,
2012). While the number of hippocampal neurons is not reduced
in mice surviving abdominal sepsis, there is neuronal degenera-
tion (Yokoo et al., 2012), and the spine density of CA1 neurons
is significantly diminished, and this finding correlates with circu-
lating HMGB1 (Chavan et al., 2012). Anti-HMGB1 neutralizing
monoclonal antibodies improve the memory deficit observed in
experimental sepsis, although the mechanism of neuroprotection
behind this protective effect is still under investigation. In response
to systemic LPS, cortical mRNA expression of IL-1β, IL-6, TLR2,
TLR4, Scavenger A, and glial fibrillary acidic protein (GFAP) are
upregulated within 4 h, indicating that cortical inflammation and
glial activation occur in parallel or shortly after systemic inflam-
mation ensues (Noh et al., 2014;Silverman et al., 2014). LPS also
increased brain mitochondrial complex II/III activity,and reduced
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Sankowski et al. Systemic inflammation and neurodegeneration
FIGURE 2 | Connectome of the human brain.The human brain is organized
as a small-world network. Neurons (black dots) form functional modules (gray
shaded area). Within such modules, high connectivity is established by short
intramodular connections (black lines). Additionally, long intermodular
connections located in the white matter (red lines in yellow shaded area)
connect different modules with each other. Small-world networks ensure
parallel processing of different modes of information within specialized
functional modules. Long intermodular connections (red lines) integrate
different kinds of information to code a complex response by the brain. The
“wiring cost” of neuronal connections is determined by the energetic
requirements to maintain these connections. Short intramodular connections
have low wiring costs (black line). Long intermodular connections ensure high
network efficiency through parallel information processing at the expense of
high wiring costs (red line). High wiring cost renders long intermodular
connections (red lines) susceptible to energetic imbalance caused by
systemic inflammation. Figure modified after Watts and Strogatz (1998).
brain glutathion levels within 1 h after systemic administration,
supporting the role of systemic inflammation in cerebral mito-
chondrial dysfunction in sepsis (Noh et al., 2014). Interestingly,
even a single and relatively low dose of LPS (that is sufficient to
cause around 10% mortality) has been shown to have long-term
behavioral and cognitive consequences. In one study, 30-day eval-
uation showed increased anhedonia and anxiety, altered working
memory, as well as reduced exploratory behavior (Anderson et al.,
2015). Consistent with that, in a model of endotoxemia in aged
rats, a single systemic injection of LPS induced brain inflamma-
tion that lasted for at least 30 days. Interestingly, those rats had
only transient increase of circulating TNF and IL-1 lasting <6 h
in response to the injection (Fu et al., 2014). The hippocampus
and dentate gyrus were particularly affected, showing astrogliosis
and increased TNF, IL-1, and NF-κB mRNA and protein levels.
This suggests that even transient bouts of systemic inflammation
of only limited significance can cause sustained brain damage.
Delirium and brain dysfunction can be induced directly by
soluble mediators such as TNF, IL-1, or HMGB1, as well as indi-
rectly through activation of microglia and astrocytes. LPS has been
shown to induce microglial activation and memory impairment
in young mice through a mechanism that is at least partially
dependent on interleukin (IL)-1, and HMGB1, both occurring
within 24 h of LPS administration (Terrando et al., 2010a). How-
ever, while the rapid effect of LPS upon brain homeostasis is
clear, a single sublethal injection of LPS (5 mg/kg) is sufficient to
impair behavior and memory, mediated by a reduction in neural
stem cell proliferation in the dentate gyrus, as well as inducing
microglia invasion and activation to the hippocampus, all lasting
for at least 30 days (Anderson et al., 2015). Minocycline, a tetra-
cycline derivative used commonly for acne and other infections,
inhibits activation and proliferation of microglia (Tikka et al.,
2001). Intracerebroventricular (ICV) administration of minocy-
cline immediately after sepsis induction by CLP reduced cerebral
inflammation, decreased BBB permeability, and protected against
memory impairment observed in untreated septic mice (Michels
et al., 2015).
SUSCEPTIBLE BRAIN: PREDISPOSING FACTORS DRIVE
NEURODEGENERATION
While the nervous system is susceptible to peripheral challenges,
one question under active research concerns to the role of a
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Sankowski et al. Systemic inflammation and neurodegeneration
susceptible nervous system. Genes and molecular factors render-
ing rodents and humans prone to neurodegeneration have been
identified recently. Genes predisposing to neurodegeneration are
summarized in Table 1. The mouse strain DBA/2J has a natural
anxious behavior. In response to a systemic challenge with low-
dose LPS (1 mg/kg), DBA/2J mice develop increased anxiety, and
increased expression of hypothalamic mRNA expression of the
inflammatory genes Il1b,Il6,tnf, and Nos2 in comparison to behav-
iorally normal strains (Li et al., 2014), suggesting that emotional
stress has a role in magnifying a systemic inflammatory stimulus.
Sepsis-induced cognitive decline can be exacerbated in individ-
uals with a susceptible brain (Iwashyna et al., 2010). Interestingly,
in community-based patients with AD, even mild inflammatory
conditions can lead to cognitive decline and disease progression
(Holmes et al., 2009). Similarly, in a mouse model of AD, within
24 h after the systemic administration of LPS, cerebral IL-1βand
IL-6 were induced, followed by changes in β-amyloid precursor
peptide (APP) isoforms similar to those observed in AD patients
(Brugg et al., 1995). In the past few years, possible mechanisms of
damage have been proposed based on rodent models. In contrast
to healthy control mice, scrapie-infected mice – a model of prion
disease – show markedly enhanced susceptibility to LPS, leading
to altered working memory, synaptic loss, enhanced expression
of inflammatory receptors, and microglial activation (Murray
et al., 2012). Cognitive and motor coordination are more severely
impaired in mice that have been scrapie-infected for longer time
periods, and one-time inflammation seems to accelerate disease
features of neurodegeneration (Cunningham et al., 2009). More-
over, in prion disease neurodegeneration occurring in response to
systemic inflammation is proportional to the burden of preexist-
ing neurodegeneration. In a rat model of toxin-induced Parkinson
disease (PD) induced by 6-hydroxydopamine, persistent systemic
inflammation induced by IL-1βresulted in a reduction in the num-
ber of neurons, as well as an increase in activated microglia in the
substantia nigra (SN) (Pott Godoy et al., 2008). The damage to
SN in response to inflammation is not limited to susceptible ani-
mals. In response to systemic LPS, 8-month-old wild type mice
showed a rapid reduction of tyrosine hydroxylase (dopaminer-
gic) neurons, with a reciprocal expansion in activated microglia
in the SN occurring shortly thereafter (Reinert et al., 2014). Amy-
otrophic lateral sclerosis (ALS) is a neurodegenerative disorder
characterized by progressive, irreversible, and highly lethal motor
neuron damage. In transgenic mice expressing a mutant form of
superoxide dismutase 1 (SOD1), an experimental model of ALS,
inflammation in the anterior horns of the spinal cord is a hallmark.
Inflammation is driven by tissue-resident microglia displaying a
neurodegeneration-specific pattern of gradual increase in insulin-
like growth factor 1 (Igf1) and the tyrosine kinase receptor AXL
(Axl) transcription that closely correlate with disease progres-
sion (Chiu et al., 2013b). The activated microglia induce motor
neuron death through induction of NF-κB (Frakes et al., 2014).
The peripheral nervous system of SOD1 mutant mice also dis-
plays inflammation that is proportional to disease progression;
in this case, there is invasion of the anterior (motor) roots by
circulation-derived active macrophages (Chiu et al., 2009). While
spinal cord inflammation may be common in SOD1 mutant mice,
those mice display an increased susceptibility to chronic systemic
inflammation, leading to disease progression, induction of TLR2,
early axonal damage, and accelerated mortality (Nguyen et al.,
2004). Although the mechanism for increased susceptibility to
systemic inflammation in SOD1 mutant mice is unknown, it is
possible that persistent systemic inflammation can further activate
microglia and induce the translocation of NF-κB and activation
of downstream inflammatory mediators.
Altogether, current evidence indicates that cognitive impair-
ment is common in sepsis; that a susceptible brain is fertile ground
for systemic inflammatory-induced dysfunction; and that cogni-
tion and behavior are persistently challenged, even after resolution
of acute sepsis.
SYSTEMIC LUPUS ERYTHEMATOSUS: SYSTEMIC
AUTOIMMUNE INFLAMMATION AS DRIVER OF
NEURODEGENERATION
Systemic lupus erythematosus (SLE) is a chronic relapsing–
remitting autoimmune disease that affects multiple organs and
often involves the central nervous system (CNS). It has a high
female preponderance and occurs mainly in women of child-
bearing age. Immunologically, it is characterized by a loss of
tolerance to self-antigens and abnormal B- and T-cell responses.
Immunoglobulin complexes can deposit in tissue and can cause
systemic inflammation. Anti-nuclear antibodies can be found
in up to 98% of patients, yet can also be detected in other
autoimmune conditions. Neuropsychiatric SLE (NPSLE) is an
incompletely understood medical problem, and its clinical pic-
ture diverse. Depending on the study, the percentage of patients
with neurological and psychiatric involvement can vary from
12 to 95% (Ainiala et al., 2001). CNS involvement indicates a
more severe clinical presentation of SLE (Mak et al., 2012). Due
to the wide range of motor, sensory, cognitive, and behavioral
symptoms, diagnosis of neuropsychiatric symptoms is challenging
(Jeltsch-David and Muller, 2014). Memory impairment is linked
to neuronal cell death in the hippocampus, and might be caused
by antibody mediated cytotoxicity following binding to neuronal
cell surface receptors, such as the NMDA receptor (Faust et al.,
2010) or neuronal surface P antigen (NSPA) (Bravo-Zehnder et al.,
2015). Cognitive impairment in NPSLE has been associated with
a higher frequency of hippocampal atrophy (Appenzeller et al.,
2006). There is a great set of data demonstrating that neuropsy-
chiatric symptoms could be caused by autoantibodies, cytokines
or microvasculopathy, and thrombosis. The most common brain
abnormalities in patients include microvasculopathy, which can be
caused by antiphospholipid antibodies that bind to clotting factors
and endothelial cells (Belmont et al., 1996). In addition to vascu-
lopathy, post-mortem brain studies of patients show infarcts and
hemorrhages, cortical atrophy, ischemic demyelination, as well as
CNS demyelination (Hanly et al.,1992). Currently,it is not known
whether CNS involvement develops independently or occurs as a
consequence of systemic organ dysfunction or both. Neurological
involvement might be related to treatment, infection, or meta-
bolic disorders or may be part of a coexisting disease. Increased
BBB permeability leads to CNS penetration of immunoglobulin,
pro-inflammatory cytokines, and albumin. A limited number of
studies addressed the genetics of NPSLE, and found an increased
susceptibility in patients with brain involvement compared to SLE
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Sankowski et al. Systemic inflammation and neurodegeneration
sparing CNS involvement. Particularly TREX 1 (DNase III) gene
mutations have been reported in NPSLE (Table 1;Lee-Kirsch
et al., 2007b;de Vries et al., 2010), a mutation that is also found
in other brain diseases and is involved in apoptosis and oxida-
tive stress. TREX 1 knockout mice develop severe inflammatory
myocarditis,resulting in reduced survival rates (Morita et al., 2004)
due to accumulation of single stranded DNA fragments, which
facilitates the production of type 1 IFN (Miner and Diamond,
2014). Larger genome wide association studies (GWAS) compar-
ing patients with and without neuropsychiatric involvement are
needed to further understand NPSLE. Despite improved imag-
ing and the availability of potential biomarkers (autoantibodies,
cytokines, chemokines), NPSLE remains a diagnostic dilemma.
So far, no specific treatment is available for NPSLE; however,
the CD20 B-cell targeted treatment rituximab was shown to be
promising in a small cohort of refractory NPSLE patients (Toku-
naga et al., 2007). In addition, peptide mimotopes in patients with
anti-brain reactive antibody responses may hold promise (Bloom
et al., 2011).
MULTIPLE SCLEROSIS: BRAIN INFLAMMATION AS DRIVER
OF NEURODEGENERATION
Multiple sclerosis (MS) is the most common inflammatory
demyelinating diseases in young adults with a high risk of
long-term disability affecting over 2.5 million people worldwide
(Compston and Coles, 2008). Despite advances in diagnosis and
treatment, the cause of MS remains unknown. While effective
treatment for the relapsing–remitting form has improved signifi-
cantly,treatment for the progressive disease course is still of limited
utility (Lassmann et al., 2007). MS is presumably caused by an
exogenous trigger in genetically predisposed individuals (Sospedra
and Martin, 2005b), resultingin inflammation, demyelination, and
neurodegeneration. MS is initiated by autoreactive T-cells against
a yet unknown CNS antigen (Sospedra and Martin, 2005a). In
addition to T-cells, in the last years, an important role of B-cells
and antibodies has re-emerged as major contributors to the dis-
ease (Hauser et al., 2008). Experimental autoimmune encephalitis
(EAE), the most widely used animal model for studying MS (Friese
et al., 2006) is either induced by injection of myelin derived pro-
teins together with adjuvant or by adoptive transfer of CD4+
encephalitogenic T-cells. It has been increasingly recognized that
this model does not accurately represent the full spectrum of the
human disease. MS is a heterogeneous disease, with patients expe-
riencing a broad range of motor, cognitive, and neuropsychiatric
impairment (Chiaravalloti and DeLuca, 2008). Approximately
80% of patients develop relapsing–remitting MS (RRMS), where
patients experience relapses that are followed by partial or com-
plete remission (Sospedra and Martin, 2005a). In an advanced
disease stage, the majority of RRMS patients convert to secondary
progressive MS (SPMS), with a steady disease progression in the
absence of relapses and remissions (Sospedra and Martin, 2005b).
A minority of patients (15%) suffer from an early onset progressive
neurological decline, defined as primary progressive MS (PPMS)
(Sospedra and Martin, 2005a,b;Miller and Leary, 2007). PPMS
presentation is similar to that of SPMS patients (Confavreux and
Vukusic, 2006). Since the progressive disease is not associated with
the number of relapses or the extend of inflammation (Friese et al.,
2014), it remains unknown what drives neurodegeneration in MS.
So far, the interplay, timing, and localization of inflamma-
tion, breakdown of the BBB, demyelination, axonal dysfunction,
neurodegeneration, gliosis, atrophy, and repair mechanisms are
incompletely understood (Figure 1) (Noseworthy et al., 2000;
Bruck, 2005). The pathological hallmark of MS is CNS plaques,
which are areas of focal demyelination in the white matter
(Popescu and Lucchinetti, 2012). Whereas glial scarring was
described as a characteristic feature of demyelinating plaques,
most studies used to emphasize an initial preservation of axons.
During RRMS, focal lesions, which are disseminated in space and
time (McFarland and Martin, 2007), are associated with a BBB
breakdown and an infiltration and activation of immune cells
(Sospedra and Mart in, 2005b). Lesions can be completely or partly
resolved due to remyelination and resolution of inflammation. In
contrast, the progressive disease stage results in irreversible deficits
and is pathologically characterized by chronic axonal degeneration
and gliosis. Although demyelination is described as primary event
in MS, and neurodegeneration is believed to occur as a secondary
event, it is now widely accepted that axonal loss occurs already in
acute white matter plaques (Bruck and Stadelmann, 2003). MS was
believed to be primarily a white matter disease, yet cortical gray
matter lesions and atrophy in the brain and spinal cord can be
observed at different time points of the disease, even as early as at
the time of diagnosis (Peterson et al., 2001;Bø et al., 2003;Kutzel-
nigg et al., 2005, 2007;Geurts et al., 2007;Barkhof et al., 2009).
In addition, the marker for neuronal integrity N-actetylaspartate
(NAA) is decreased throughout the CNS at an early disease stage
(De Stefano et al., 2001). NAA levels are also decreased in the
normal appearing white matter and in the cortical gray mat-
ter. Increased concentrations of the neurofilament protein in the
cerebrospinal fluid (CSF) can be observed at all stages of the dis-
ease, which additionally reflects early ongoing neurodegeneration
(Kuhle et al., 2011).
While there has been major progress in treating RRMS with
anti-inflammatory and immunomodulatory treatment, there are
currently no effective treatment options for the progressivedisease.
The inefficiency of anti-inflammatory treatment in PPMS and
SPMS was explained by the lack of inflammation during neurode-
generation. However, this could be due to impaired drug delivery
to the brain due to a widely restored BBB integrity in the pro-
gressive disease stage (Lassmann et al., 2012). In contrast to the
traditional view that neurodegeneration in MS occurs in the pres-
ence of limited or almost absent inflammation, it has been shown
that inflammation is present at all stages of the disease (Frischer
et al., 2009). In fact, there is a massive infiltration of microglia
and immune cells into gray matter lesions, including the deep gray
matter (Lucchinetti et al., 2011). However, chronic lesions in the
gray matter show less extend of immune cell infiltration compared
to chronic white matter lesions (Popescu and Lucchinetti, 2012).
Cortical lesions can be observed even before detection of white
matter lesions. Most patients have the highest prevalence of corti-
cal lesions in the progressive disease stage, where diffuse meningeal
inflammation correlates with the disease severity, suggesting that
cytokines, chemokines, reactive oxygen species (ROS), and gluta-
mate released by meningeal infiltrating immune cells contribute to
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Sankowski et al. Systemic inflammation and neurodegeneration
neurodegeneration by disturbing the neuronal metabolic pathway
(Friese et al., 2014). A redistribution of ion channels could be a
compensatory effect of the inflamed axon but finally accelerates
neurodegeneration.
Overall, the cause and mechanism of neurodegeneration in
MS is unresolved, yet it is highly likely that there is a large
variability within individual subgroups of MS patients. In some
patients, inflammation can be caused by primary neurodegener-
ation, whereas demyelination can be the primary cause in others,
causing axonal transection and thereby initiating Wallerian and
retrograde neurodegeneration (Friese et al., 2014). It has been
shown that demyelination can lead to axonal degeneration and
neuronal loss by limited trophic support of oligodendrocytes
(Fünfschilling et al., 2012;Lee et al., 2012). Neurodegeneration
in MS can also occur, at least partly, in the absence of demyeli-
nation since axonal and neuronal injury in the normal appearing
white matter is rather associated with global CNS inflammation
but not with white matter demyelination (Friese et al., 2014). The
continuous worsening of the disease can be explained by progres-
sive neuronal loss, which cannot be compensated over time by
protective repair mechanisms. However, the total lesion load does
not correlate with the extent of neurodegeneration, suggesting that
neurodegeneration is the result of inflammatory processes in non-
lesioned white matter.Alternatively, MS can be a primary neurode-
generative disease rather than an autoimmune disease (Trapp and
Nave, 2008). However, genetic findings show no correlation of
genetic risk alleles in MS with other neurodegenerative diseases. A
role of genetic heritability in MS was supported by early findings,
which observed aggregations of MS cases in some families as well
as an increased prevalence of MS in monozygotic twins compared
to dizygotic twins (Ebers et al., 1995). Genetic susceptibility genes
have been described but the disease does not follow a Mendelian
inheritance pattern but a rather complex pattern of interaction.
The most striking findings regarding genetic susceptibility in MS
comes from studies obtained in the 1970s showing an associa-
tion of MS with alleles of the MHC, particularly HLA-DRB1*15,
of the class II gene HLA-DRB1, which is the most important
risk allele in MS. GWAS and meta analysis enabled the discov-
ery of many single nucleotide polymorphisms (SNIP) in MS. To
date, around 350 MHC and non-MHC loci have been identified
(Wang et al., 2011), which are mainly involved in immunological
processes (Wang et al., 2011). Some of those risk genes overlap with
other autoimmune diseases, whereas other risk genes are unique
to MS. Based on the current studies, the genetic risk for MS is
not linked to a single gene mutation but rather caused by a com-
plex interplay of many SNIP, which amplify and result in small or
moderate risk effects. MS is probably caused by a multifactorial
pattern of inheritance, which needs further investigation in indi-
vidual larger patients groups. Once GWAS studies identify SNIPs
in MS patients, there is a great interest to correlate these findings
with functional data. Prime examples are the findings of SNIPS
in the TNFRSF1A gene that have been associated with a worse
clinical outcome in MS patients. This mutation results in a novel
soluble splice form of the TNF receptor (TNFR1) that, in contrast
to the membrane bound form, lacks NF-κB activity and apoptotic
activity but can block the function of TNF and thus mimics anti
TNF therapies, which exacerbate MS (Gregory et al., 2012).
So far, most genetic studies focus on genes responsible for
the initiation of the disease rather than on genes influencing the
severity of the disease (Friese et al., 2014). Thus, future studies
are needed to identify genes that trigger the progression of the
disease in the presence of inflammation. One study showed that
meningeal inflammation is associated with small fiber axonal loss
in the spinal cord of patients that were HLA-DRB1*15 positive,
correlating neurodegeneration with increased genetic suscepti-
bility (DeLuca et al., 2013). Another study demonstrated higher
glutamate levels in the brain of MS patients harboring certain
risk alleles for genes involved in the glutamate pathway (Baranzini
et al., 2010). A polymorphism of the inositol polyphosphate-4-
phosphatase, type II (Inpp4b), which was described for MS results
in decreased nerve conduction velocity, which could aggravate the
disease (Lemcke et al., 2014). More GWAS studies are needed
to confirm these results and there should be a particular focus
on polymorphisms associated with the progressive disease stage.
In addition to genetic susceptibility genes, several environmental
factors have been suggested to trigger the disease, such as vita-
min D, smoking, Epstein–Barr virus infection, and geographical
location in relation to latitude gradient (Ascherio and Marrie,
2012).
MECHANISMS OF NEURODEGENERATION: SYSTEMIC
INFLAMMATION DRIVES DISRUPTION OF BRAIN NETWORKS
Biological systems, such as the neuronal network of the human
brain (Sporns et al., 2005;Achard et al.,2006;Bullmore and Sporns,
2009) have “small-world” properties (Watts and Strogatz, 1998).
Small-world networks have two levels of organization (Figure 2).
On the local level, groups of neurons specialized in a specific task
form functional modules with high short intramodular connectiv-
ity. On the global level, different modules are connected through
long intermodular connections. The advantage of the latter type
of connections is enhanced computational efficiency through par-
allel processing of information (Watts and Strogatz, 1998;Latora
and Marchiori, 2001;Bullmore and Sporns, 2009). Anatomically,
long intermodular connections are formed by axonal fiber tracts
in the white matter (Bullmore and Sporns, 2009;Toga et al.,
2012). Long fibers are characterized by high energetic “wiring
costs” (Bullmore and Sporns, 2012). To provide the energy for
the maintenance of these long fibers the brain is relying on a
constant energy supply. Recent findings have elegantly identified
oligodendrocyte-derived lactate as the main energetic substrates
for axonal maintenance (Fünfschilling et al., 2012). Consistently,
disruption of this oligodendrocyte-neuronal metabolic coupling
triggered neurodegeneration (Lee et al., 2012). Systemic inflam-
mation poses dramatic challenges to the energetic supply of the
brain.
To cover its wiring costs the brain is highly reliant on a
constant nutrient supply. Nutrient supply through blood ves-
sels can be compromised through vascular pathologies associated
with systemic inflammation. During severe sepsis, disseminated
intravascular coagulation leads to diffuse intravascular formation
of thrombi and hemorrhages due to depletion of coagulation fac-
tors. The consequences are diffuse ischemic foci throughout the
body and dysfunction of affected organs. Infarctions or hemor-
rhages occurring in the course of long connecting tracts in the
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Sankowski et al. Systemic inflammation and neurodegeneration
brain lead to disconnection of distant brain regions and reduced
efficiency of neuronal networks. These changes might contribute
to white matter lesions observed in MRI studies of acute sepsis
cases (Sharshar et al., 2007) and sepsis survivors (Morandi et al.,
2012;Semmler et al., 2013). Mitochondrial dysfunction is another
complication of sepsis affecting brain function. Despite normal or
even increased tissue oxygen availability (Boekstegers et al., 1991),
oxygen utilization is drastically reduced in critically ill patients
leading to multi-organ failure and mortality (Brealey et al., 2002).
Brain mitochondrial dysfunction was shown in rodent models of
sepsis (d’Avila et al., 2008). This hibernation-like metabolic state
was proposed as a physiological protective tissue reaction (Singer
et al., 2004). However, mitochondrial dysfunction might persist
in sepsis survivors (Comim et al., 2011). The cause for mitochon-
drial dysfunction might be a combination between induction of
ROS during sepsis (Wong et al., 1996) and impaired mitochon-
drial turnover (Singer, 2014). Taken together, the complicated
interrelation between focal hypoperfusion and reduced oxygen
utilization lead to a complex acute and chronic phenotype referred
to as sepsis-associated encephalopathy (Gofton and Young, 2012;
Sonneville et al., 2013).
Autoimmune disorders have a chronic course of vascular
pathology with acute flares. The most common vascular pathology
is the autoantibody-associated antiphospholipid syndrome (Ben
Salem, 2013;Giannakopoulos and Krilis, 2013;Million and Raoult,
2013). Patients with antiphospholipid syndrome display cogni-
tive deficits (Gómez-Puerta et al., 2005;Tektonidou et al., 2006).
MRI studies found diffuse infarctions and white matter lesions in
these patients (Gómez-Puerta et al., 2005;Tektonidou et al., 2006;
Valdés-Ferrer et al., 2008). The role of mitochondrial dysfunc-
tion in autoimmune diseases is not clear. In SLE, mitochondrial
dysfunction and ATP depletion were shown as triggers of lym-
phocytic cell death (Gergely et al., 2002). An interesting view of
mitochondrial dysfunction in the context of MS was recently pro-
posed (Lassmann, 2011). In line with the concept of high “wiring
costs” imposed on the brain by long intermodular connections
(Bullmore and Sporns, 2012), Hans Lassmann argues that inflam-
mation in MS causes mitochondrial damage and inability of the
brain to maintain neuronal processes. The sourceof mitochondrial
damage is radicals formed as a consequence of inflammation in MS
(Lassmann, 2011;Fischer et al., 2012). Disruption of neuron–glia
metabolic coupling might be another potential mechanism caus-
ing neurodegeneration and network disruption (Allaman et al.,
2011;Lee et al., 2012).
Taken together these findings indicate that systemic inflam-
mation leads to an energy crisis of the brain that reduces its
connectivity. Oxidative stress might be the main mediator of
this pathology. Thus, inflammation-induced changes in the brain
resemble hallmarks of the aged brain where oxidative damage
leads to decreased expression of genes associated with synaptic
plasticity and increased expression of stress-response genes (Lu
et al., 2004). Likewise, the brain during systemic inflammation
shows hallmarks of neurodegenerative diseases where oxidative
stress and mitochondrial damage have consistently been found
(Lin and Beal, 2006). Studies with bigger sample sizes are needed
to identify common mechanisms between systemic inflammation,
brain aging, and neurodegeneration.
SYSTEMIC INFLAMMATION-ASSOCIATED
IMMUNOPATHOLOGY IRREPARABLY DAMAGES THE
ARCHITECTURE OF THE BRAIN
With approximately 90 billion neuronal and non-neuronal cells,
respectively (Azevedo et al., 2009), the human brain is charac-
terized by high architectural complexity (Braitenberg and Schüz,
1991). Due to this complexity, the repair capacity is limited ren-
dering the human brain highly susceptible to tissue damage. As
primary preventive measures the brain is protected from differ-
ent modes of tissue damage; for example, by the skull bone from
mechanical damage or by the BBB from blood-borne pathogens.
The BBB is mainly formed by endothelial cells and astrocytes
(Abbott et al., 2006;Weiss et al., 2009); the formation of tight
junctions between endothelial cells forms a highly selective bar-
rier that becomes more permeable during systemic inflammation
(McColl et al., 2008;Weiss et al., 2009). A third kind potential
source of brain tissue damage is the immune system itself. As
pathogen defense is invariably associated with host tissue dam-
age (Graham et al., 2005) an anti-inflammatory milieu preserves
the brain from aberrant immune activation. Under physiological
conditions, astrocytes and neurons actively modulate the activa-
tion of brain immune cells (Neumann, 2001;Tian et al., 2012).
Through this cross-talk brain cells can actively recruit immune
cells for purposes of brain homeostasis such as synaptic plasticity,
induction of inflammation, clearance of debris, and resolution of
inflammation.
Brain-resident microglia and peripheral immune cells maintain
immune surveillance of brain parenchyma, CSF, and perivascular
space for infectious agents or damage-associated milieu changes
(Ousman and Kubes, 2012;Ransohoff and Engelhardt, 2012). In
the case of brain infection, complete eradication of some invading
pathogens can only be achieved at the cost of irreparable damage
to brain tissue. To prevent such damage, the immune system has
established active mechanisms of pathogen tolerance (Medzhitov
et al., 2012). Examples for coexistence-prone pathogens are herpes
simplex virus type I (Khanna et al., 2004) or Cryptococcus gattii
(Cheng et al., 2009). A growing body of evidence indicates that not
only immune tolerance but also resolution of neuroinflammation
is a tightly regulated active immunological process (Schwartz and
Baruch, 2014). Taken together, anti-inflammatory brain milieu,
pathogen tolerance, and resolution of neuroinflammation require
a balanced action between different branches of the immune sys-
tem. An imbalance within the immune system leading to systemic
inflammation may be a driver of neurodegeneration through the
mechanisms discussed below.
CASPASES AS MEDIATORS OF INFLAMMATION AND
NEURODEGENERATION
Apoptosis is one of the main drivers of neurodegeneration. Apop-
tosis and cell death constantly occur under physiological condi-
tions throughout the human body and cell debris is cleared by
immune cells mostly without induction of chronic inflamma-
tion (Green et al., 2009). However, during systemic inflammation,
apoptosis of stressed cells might further exacerbate the underly-
ing pathology (Zitvogel et al., 2010). Activators of apoptosis lead
to direct or indirect activation of caspases. Interestingly, caspases
are not only classical executors of apoptosis (Friedlander, 2003)
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Sankowski et al. Systemic inflammation and neurodegeneration
but also inflammatory caspases are crucial for the activation of the
innate immune system through the inflammasome (Martinon and
Tschopp, 2004). Caspase-1, as the cleaving enzyme for IL-1βand
constituent of the inflammasome, is the prototypic representative
of the latter class of caspases (Martinon et al., 2002).
Activation of the innate immune system through the inflamma-
some is a driver of pathology in age-associated and autoimmune
neurodegenerative disorders. In AD, the NLRP3 inflammasome
was described a sensor of β-amyloid (Heneka et al., 2013). Of
interest, deletion of Caspase-1 or NLRP3 rescued the phenotype in
APP/PS1 AD transgenic mice (Heneka et al., 2013). Consistently
with that the deletion of the inflammasome scavenger receptor
CD36 (Sheedy et al., 2013) ameliorated pathology in the Tg2576
AD mouse model (Park et al., 2013). MS-like lesions were found in
humans with mutations of proteins associated with the inflamma-
some (Compeyrot-Lacassagne et al., 2009). Additionally, NLRP3
and IL-1 knockout mice had decreased pathology following EAE
(Matsuki et al., 2006;Gris et al., 2010).Approved clinical treatment
options of MS such as IFN β(Guarda et al., 2011) or glatiramer
acetate (Burger et al., 2009) have been shown to decrease IL-1β
levels, the main cytokine processed by the inflammasome. Addi-
tionally,novel evidence extends the functions of the classical apop-
totic caspases linking neuroinflammation to neurodegeneration.
Activation of microglial caspase-8, -3, and -7 can drive neurode-
generation (Burguillos et al., 2011). Finally, recent evidence from
C. elegans has descr ibed protective effects through mediators of the
intrinsic apoptosis pathway against ROS (Yee et al., 2014). Taken
together, these finding show an intricate relationship between
inflammation and activation of apoptosis. However, the definite
role of these mediators in the brain remains to be characterized.
MICROGLIA- AND MACROPHAGE-DERIVED MICROVESICLES
AS INDUCERS OF NEURODEGENERATION
Cellular components of innate immunity can pack and secrete
inflammatory messengers in microvesicles (MVs). Peripheral
macrophages, as well as brain microglia can secrete inflamma-
some components (caspase-1, IL-1β, and IL-18) in MVs, and the
presence of extravesicular inflammatory inducers (e.g., astrocitic
ATP) is sufficient to induce the neurotoxicity by the inflammatory
load of MVs (Bianco et al., 2005;Sarkar et al., 2009;Gulinelli et al.,
2012). Although MVs are visible in the CSF in healthy controls,
the load of MVs in RRMS, neuromyelitis optica (NMO), brain
infections, and brain tumors is significantly increased and, in MS,
correlates with disease activity (Verderio et al., 2012). Recent evi-
dence suggest that MVs play a critical role in the spectrum of
AD as well. MVs released by activated microglia participate in the
neurodegenerative process of AD by promoting the generation of
highly neurotoxic soluble forms of β-amyloid (Joshi et al., 2014).
Based on this collective evidence, it is now clear that EVs pro-
duced by peripheral myeloid cells, as well as immune brain cells,
are novel and potentially critical biomarkers for neuroinflamma-
tory conditions by providing a link between inflammation and
neurodegeneration.
IMMUNE CELLS AND IMMUNE MEDIATORS AS DRIVERS OF
NEURODEGENERATION
Various triggers of apoptosis have been described with respect
to the brain. Neuronal apoptosis can be directly induced by
ROS, pro-inflammatory cytokines or activated immune cells. The
consequences of ROS-induced mitochondrial damage on brain
metabolism have been discussed above. Additionally, damaged
mitochondria are a major source of ROS (Rego and Oliveira,
2003) and mediators of apoptosis (Green and Kroemer, 2004).
Conversely, inactivation of ROS has anti-apoptotic effects (Hock-
enbery et al., 1993;Greenlund et al., 1995). The inflammatory
cytokine TNFα(Tamatani et al., 1999;Kaur et al., 2014) and tumor
necrosis factor-related apoptosis-inducing ligand (TRAIL) (Aktas
et al., 2005) directly induce neuronal apoptosis (Figure 3). Addi-
tionally, intracerebroventricularly injected TNFαwas shown to
induce depression-like symptoms (Kaster et al., 2012). Cytokine
mediated induction of apoptosis was also observed by IL-1β(Wang
et al., 2005;Kaur et al., 2014). Sources of cytokines under sys-
temic inflammation are brain resident, paravascular or periph-
eral immune cells (Dantzer et al., 2008). Furthermore, activated
immune cells can directly induce neuronal cell death (Figures 1
and 3). Brain-resident microglia convey neuronal toxicity through
various mechanisms including secretion of neurotoxic factors (Liu
and Hong, 2003;Block et al., 2007), as well as through activation of
cyclooxygenase/prostaglandin E2 (COX/PGE2) pathways (Mon-
tine et al., 1999;Liang et al., 2005). In fact, blocking the COX/PGE2
pathway by experimentally deleting the prostaglandine receptor
EP2 increases mitochondrial degradation of β-amyloid, poten-
tially opening a new therapeutic avenue for AD (Johansson et al.,
2015).
Peripheral immune cells can penetrate the BBB under condi-
tions of systemic inflammation (Schmitt et al., 2012) and con-
tribute to brain pathology (Rezai-Zadeh et al., 2009) (Figure 3).
Cytotoxic T-cells were shown to be directly neurotoxic in autoim-
mune and aging-associated neurodegenerative disorders of the
CNS (Neumann et al., 2002). Co-localization of T-cells with neu-
rons and neuron-specific cytotoxicity of T-cells was shown in vivo
and in vitro (Giuliani et al., 2003;Nitsch et al., 2004). The piv-
otal role of pathogenic T-cells in MS is suggested by the fact
that adoptive transfer of myelin reactive T-cells is sufficient to
induce EAE in rodents. Finally, B-cells have multiple roles in MS
(Krumbholz et al., 2012). On the one hand, B-cells can serve as
antigen presenting cells for T-cells and B-cell derived cytokines
can activate pathogenic T-cells (Schneider et al., 2011). On the
other hand, intrathecal IgG synthesis and persistent oligoclonal
bands in the CSF are a hallmark finding in MS. Furthermore,
antibodies and complement deposition is present in acute MS
lesions (Lucchinetti et al., 2000). B-cells were shown to mature
in the draining cervical lymph nodes and migrate to the brain
(Stern et al., 2014). With advancing pathology, B-cells can be
found in serum, brain parenchyma,and meninges of patients (Ser-
afini et al., 2004;Kuerten et al., 2014); and B-cell depletion was
shown to be beneficial in a subgroup of MS patients (Hauser et al.,
2008).
ANTI-BRAIN ANTIBODIES AS DRIVERS OF
NEURODEGENERATION
B-cell-derived anti-brain antibodies have been identified as dri-
vers of brain pathology in various diseases. In the last decade,
an increasing number of anti-brain antibodies has been detected
that can affect cognition and behavior (Diamond et al., 2013).
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Sankowski et al. Systemic inflammation and neurodegeneration
FIGURE 3 | Inflammation leads to neurodegeneration: a simplified
model. Pathogen- or damage-derived antigens released in sufficient
quantity activate systemic inflammation. In turn, peripheral (e.g.,
monocytes) as well as central (e.g., microglia) immune cells activate,
increasing the production and release of inflammatory cytokines,
chemokines, and other immunologically active peptides.Those mediators
can induce neuronal dysfunction directly or indirectly, by interfering with
neuronal homeostasis or disrupting the neuronal milieu. The end-result is a
continuum of clinical manifestations from local and transient, to diffuse
and persistent.
For many of these newly discovered antibodies their frequency in
disease and involvement in pathogenesis has not yet been deter-
mined. Although anti-brain antibodies can be present in around
5% of healthy individuals (Diamond et al., 2013), an intact BBB
restricts entry of antibodies into the brain. Under pathological
conditions, antibodies may penetrate the BBB through differ-
ent mechanisms including local and systemic inflammation, or
antigen mediated endocytosis (Diamond et al., 2013). In addi-
tion, fenestrated endothelial cells of the circumventricular organs,
which lack the tight junction of the BBB, may facilitate entry
of antibodies into the brain parenchyma (Popescu et al., 2011);
or antibodies may be produced intrathecally by B-cells, which
migrate into the CNS.
So far, few antibodies have been confirmed to be directly
neurotoxic. The most striking evidence is provided by tumor-
associated autoantibodies causing paraneoplastic neurological dis-
orders. These antibodies are cross-reactive to neuronal antigens
expressed on cancer cells; neuronal pathology is induced through
neuronal cell death after antibody binding to neuronal antigens.
Clinically, patients present with severe neuropsychiatric symp-
toms. Rapid removal of paraneoplastic antibodies and surgical
removal of the tumor can prevent further neuronal cell death und
may reverse neurological pathology. Patients that harbor an anti-
body response to intracellular antigens have a worse response to
treatment compared to patients with antibodies to extracellular
neuronal autoantigens. This could be due to an involvement of
pathogenic T-cells, which cause irreversible neuronal cell death
(Lancaster and Dalmau, 2012).
Anti-NMDA receptor encephalitis is the most common para-
neoplastic disorder, with ovarian teratomas as the underlying
malignancy in approximately 50% of the patients (Dalmau et al.,
2011). These antibodies bind the extracellular domain of the
NMDA receptor subunit 1 (GluN1) and cause psychiatric symp-
toms such as anxiety, memory loss, and psychosis (Dalmau et al.,
2007). Binding of antibodies results in reduced levels of NMDA
receptor in vitro and in vivo through antibody mediated cap-
ping, crosslinking, and internalization of the receptor (Hughes
et al., 2010), which can be reversed upon removal of the anti-
bodies (Seki et al., 2008). Interestingly, patients with high titers
of NMDA receptor antibodies have lower levels of the NMDA
receptors in postsynaptic dendrites (Dalmau et al., 2008). Direct
injection of the antibodies in the cortex of rodents results in exci-
totoxicity by increased glutamate release (Hughes et al., 2010). A
recent study found NMDA receptor antibodies in patients with
demyelinating disorders indicating that these antibodies might
cause neuropsychiatric symptoms in these patients (Titulaer et al.,
2014).
Furthermore, NMDA-receptor-specific antibodies to the sub-
unit 2 (GluN2) have been found in a subset of SLE patients
with neuropsychiatric symptoms. These antibodies are cross-
reactive to DNA and bind the consensus sequence D/E W D/E
Y S/G (DWEYS) present in the extracellular domains of GluN2A
and GluN2B subunits of the NMDA receptor (Gaynor et al.,
1997). DNA–NMDA receptor antibodies preferentially bind the
open configuration of the NMDA receptor and augment NMDA
receptor-mediated excitatory postsynaptic potentials (Faust et al.,
Frontiers in Cellular Neuroscience www.frontiersin.org February 2015 | Volume 9 | Article 28 | 11

Sankowski et al. Systemic inflammation and neurodegeneration
2010). DNA–NMDA receptor antibodies have been found in
serum, CSF, and brain tissue of SLE patients (DeGiorgio et al.,
2001;Kowal et al., 2006). Notably, patient derived DNA–NMDA
receptor antibodies cause hippocampal neuronal loss and per-
sistent memory impairment in rodents (Kowal et al., 2006).
These findings indicate that DNA–NMDA receptor antibodies
are directly involved in neurodegenerative processes in SLE. Hip-
pocampal brain abnormalities in NPSLE patients further support
this notion (Appenzeller et al., 2006). Depending on the antibody
concentrations, DNA–NMDA receptor antibodies can cause either
neuronal dysfunction by transiently enhancing excitatory postsy-
naptic potentials or can result in neuronal cell death (Kowal et al.,
2006;Faust et al., 2010). This evidence could be of high relevance in
terms of reversibility of symptoms. Furthermore, anti-brain anti-
bodies were also shown to induce neuropsychiatric symptoms in
patients with other autoimmune disorders such as celiac disease
(Alaedini et al., 2007;Hadjivassiliou et al., 2013) or inflamma-
tory bowel diseases (Häuser et al., 2011;Papathanasiou et al.,
2014). Taken together, anti-brain antibodies were shown to cause
neuropsychiatric pathology in different diseases presenting novel
therapeutic options.
These promising findings of anti-brain antibodies in systemic
inflammatory disorders encouraged the search for anti-brain anti-
bodies in inflammatory brain disorders. MS is characterized by
oligoclonal bands in the CSF and antibodies in acute MS lesions
(Lucchinetti et al., 2000). Histopathological studies confirm anti-
body mediated demyelination (Storch et al., 1998). Despite these
findings all attempts to identify pathogenic antibodies to CNS
antigens and infectious agents in the context of MS were rather
unsatisfactory. In contrast to MS, highly specific anti-brain anti-
bodies were discovered in NMO (Lennon et al., 2005), a disease
which can closely resemble MS but requires different treatment.
Antibodies to the water channel protein aquaporin-4 (AQP4) are
detectable in around 80–90% of patients with NMO (Mader et al.,
2010;Waters et al., 2012). AQP4 is localized on astrocytic end-
feet forming the BBB. NMO is characterized by optic neuritis and
longitudinal extensive transverse myelitis over three or more verte-
bral segments, which can lead to blindness and paralysis of patients
(Wingerchuk et al., 1999;Cree, 2008). AQP4 antibody seropositiv-
ity is highly predictive for the disease (Matiello et al., 2008) and
enables early treatment of patients. This is particularly impor-
tant since IFN β, commonly used for treating MS, can worsen the
disease outcome of NMO patients (Palace et al., 2010). Patholog-
ical findings show immunoglobulin and complement deposition
around blood vessels with AQP4 specific loss in brain and spinal
cord lesions (Lucchinetti et al., 2002). Rodents develop NMO-
like lesions in the brain and spinal cord upon injection of patient
derived AQP4 antibodies in an EAE animal model (Bennett et al.,
2009;Bradl et al., 2009;Kinoshita et al., 2009). In addition, one
study showed loss of astrocytes and demyelinating lesions after
injection of AQP4 IgG into the brain together with human com-
plement (Saadoun et al., 2010). AQP4 antibodies might require the
help of encephalitogenic T-cells to breach the BBB (Saadoun et al.,
2010;Pohl et al., 2013) and in addition CNS specific T-cells may
require a local inflammatory environment for the antibodies at the
lesion site (Pohl et al.,2013). Antibodies to AQP4 bind to astrocytes
and lead to complement depend cytotoxicity as well as antibody
dependent cytotoxicity, resulting in astrocytosis (Papadopoulos
et al., 2014). Demyelination and neuronal cell death could occur
as a secondary inflammatory response, due to secretion of toxic
compounds such as nitrogen species, reactive oxygen or glutamate
by activated astrocytes (Brosnan and Raine, 2013), which could
lead to limited trophic support to myelin (Levy, 2014). Recently,
cognitive impairment has been reported in NMO (Saji et al., 2013),
yet this finding needs to be replicated in larger cohorts. The patho-
logical role of AQP4 antibodies in cortical neuronal loss at areas
of high AQP4 expression is not well understood. Although NMO
is a rather rare disease, the findings obtained from AQP4 IgG and
its contribution in glial injury, demyelination and neurodegenera-
tion could be of direct relevance for MS and related inflammatory
diseases, and will help to better understand the role of astrocytes
in inflammation and neurodegeneration.
IMMUNE-MEDIATED DISRUPTION OF THE NEUROGENIC
NICHE MAY CONTRIBUTE TO NEURODEGENERATION
A final mechanism potentially connecting systemic inflammation
and neurodegeneration is impairment of neurogenesis. Neuroge-
nesis is a central mechanism required for neuronal maintenance
and adaptive plasticity in the healthy and diseased brain (Jin
et al., 2006a). Inflammatory mediators have various effects on
neurogenesis (Whitney et al., 2009). Impairment of neurogene-
sis was shown in neurodegenerative diseases such as AD (Lazarov
and Marr, 2010) and neuropsychiatric disorders such as depres-
sion (Sahay and Hen, 2007). Interestingly, approved AD drugs
(Jin et al., 2006b;Kotani et al., 2008) and chronic antidepres-
sant treatment (Malberg et al., 2000;Santarelli et al., 2003) induce
neurogenesis. Inflammation and microglial activation is detri-
mental for neurogenesis that can be restored by anti-inflammatory
treatment (Ekdahl et al., 2003;Monje et al., 2003). Moreover,
microglia are not only involved in the maintenance of the neuro-
genic niche (Sierra et al., 2010) but also in synaptic maintenance
(Stevens et al., 2007;Parkhurst et al., 2013). Of interest, systemic
immune cells were shown to be involved in regulation of neu-
rogenesis. CD4+T-cells were shown to promote (Wolf et al.,
2009) while CD8+T-cells impair proliferation of neural prog-
enitor cells (Hu et al., 2014). An effect of B-cells on neurogenesis
was not observed (Wolf et al., 2009). These findings need to be
independently replicated. However, one may speculate that neu-
ropsychiatric symptoms elicited by chronic inflammation may be
driven by detrimental changes of neuronal homeostasis. Thus,
specific immune modulatory treatment might be beneficial.
CONCLUDING REMARKS
The immune and nervous systems have co-evolved from early
invertebrates to higher mammals, creating an intricate bi-
directional modulating dialog. The CAP is a good example of the
influence of the nervous system upon the immune response. In the
opposite direction, the activation of innate immunity in response
to serious, as well as non-life threatening, infections induces the
maturation and release of TNF, IL-1β, and other inflammatory
cytokines that in turn cause transient anorexia, malaise, depres-
sion, and other features of the sickness syndrome (Figure 3). This
is not surprising if we take into consideration that glia constitutes
no less than half of the cells in a mammalian brain.
Frontiers in Cellular Neuroscience www.frontiersin.org February 2015 | Volume 9 | Article 28 | 12

Sankowski et al. Systemic inflammation and neurodegeneration
Sustained systemic inflammation is a common feature of many
autoimmune disorders, and is present in most sepsis survivors.
Cognitive impairment is common in sepsis survivors, as well as
patients suffering from chronic inflammatory conditions. Cogni-
tion and behavior are persistently challenged, even after appar-
ent resolution of acute sepsis. Moreover, systemic inflammation
occurring in a susceptible brain (e.g., patients with AD) may
lead to even further disruption in quality of life and activities of
daily living. Up to 95% of patients with SLE develop neuropsychi-
atric dysfunction. In SLE, part of the repertoire of DNA-binding
autoantibodies cross-react with hippocampal NMDA receptors,
and – through a leaky BBB – gain access to the brain, inducing
cognitive decline and other neuropsychiatric manifestations. In
patients with rheumatoid arthritis, the baseline vagal tone of is
persistently low, suggesting a possible mechanism for persistent
inflammation. Those examples indicate that the normal neuroim-
mune cross-talk in health can become deleterious during disease,
particularly in a primed brain – one with preexistent damage.
Recently, cellular, molecular, environmental, and genetic com-
ponents have been linked to the persistent brain disfunction of
systemic inflammation. Here, we have discussed mechanistic evi-
dence for the intricate interrelation between inflammation and
neurodegeneration. Identification of druggable targets derived
from these mechanisms holds the promise to prevent long-term
disability and improve the quality of life in patients with chronic
inflammatory conditions.
ACKNOWLEDGMENTS
Simone Mader work was supported by S.L.E. Lupus Foundation.
The authors want to thank Benjamin Obholzer for the image
design.
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Conflict of Interest Statement: The authors declare that the researchwas conducted
in the absence of any commercial or financial relationships that could be construed
as a potential conflict of interest.
Received: 29 November 2014; accepted: 15 January 2015; published online: 02 February
2015.
Citation: Sankowski R, Mader S and Valdés-Ferrer SI (2015) Systemic inflammation
and the brain: novel roles of genetic, molecular, and environmental cues as drivers of
neurodegeneration. Front. Cell. Neurosci. 9:28. doi: 10.3389/fncel.2015.00028
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