Cognitive and Behavioral Consequences of Impaired Immunoregulation in Aging

Article (PDF Available)inJournal of Neuroimmune Pharmacology 7(1):7-23 · September 2011with54 Reads
DOI: 10.1007/s11481-011-9313-4 · Source: PubMed
Abstract
A hallmark of the aged immune system is impaired immunoregulation of the innate and adaptive immune system in the periphery and also in the central nervous system (CNS). Impaired immunoregulation may predispose older individuals to an increased frequency of peripheral infections with concomitant cognitive and behavioral complications. Thus, normal aging is hypothesized to alter the highly coordinated interactions between the immune system and the brain. In support of this notion, mounting evidence in rodent models indicate that the increased inflammatory status of the brain is associated with increased reactivity of microglia, the innate immune cells of the CNS. Understanding how immunity is affected with age is important because CNS immune cells play an integral role in propagating inflammatory signals that are initiated in the periphery. Increased reactivity of microglia sets the stage for an exaggerated inflammatory cytokine response following activation of the peripheral innate immune system that is paralleled by prolonged sickness, depressive-like complications and cognitive impairment. Moreover, amplified neuroinflammation negatively affects several aspects of neural plasticity (e.g., neurogenesis, long-term potentiation, and dendritic morphology) that can contribute to the severity of neurological complications. The purpose of this review is to discuss several key peripheral and central immune changes that impair the coordinated response between the immune system and the brain and result in behavioral and cognitive deficits.

Figures

INVITED REVIEW
Cognitive and Behavioral Consequences of Impaired
Immunoregulation in Aging
Angela W. Corona & Ashley M. Fenn &
Jonathan P. Godbout
Received: 11 July 2011 / Accepted: 7 September 2011
#
Springer Science+Business Media, LLC 2011
Abstract A hallmark of the aged immune system is
impaired immunoregulation of the innate and adaptive
immune system in the periphery and also in the central
nervous system (CNS). Impaired immunoregulation may
predispose older individuals to an increased frequency of
peripheral infections with concomitant cognitive and
behavioral complications. Thus, normal aging is hypothe-
sized to alter the highly coordinated interactions between
the immune system and the brain. In support of this notion,
mounting evidence in rodent models indicate that the
increased inflammatory status of the brain is associated
with increased reactivity of microglia, the innate immune
cells of the CNS. Understanding how immunity is affected
with age is important because CNS immune cells play an
integral role in propagating inflammatory signals that are
initiated in the periphery. Increased reactivity of microglia
sets the stage for an exaggerated inflammatory cytokine
response following activation of the peripheral innate
immune system that is paralleled by prolonged sickness,
depressive-like complications and cognitive impairment.
Moreover, amplified neuroinflammation negatively affects
several aspects of neural plasticity (e.g., neurogenesis, long-
term potentiation, and de ndritic morphology) that can
contribute to the severity of neurological complications.
The purpose of this review is to discuss several key
peripheral and central immune changes that impair the
coordinated response between the immune system and the
brain and result in behavioral and cognitive deficits.
Keywords Aging
.
Neuroinflammation
.
Microglia
.
Fractalkine
.
Immunity
.
Immunosenescence
Introduction
The coordinated response between the immune system and
the brain is critical in the appropriate physiological,
immunologic and behavioral responses to infectious chal-
lenges. This communication requires a functional peripheral
immune system to respond to challenges and the use of
cytokine-mediated signals to alert the central nervo us
system (CNS). Moreover, signals that are initiated in the
periphery are propagated and interpreted within the CNS to
elicit key physiological (e.g., increased fever and a shift in
energy expenditure), behavioral (e.g., increased sleep and
social withdrawal) and feedback responses (e.g., activation
of hypothalamic pituitary adrenal axis, HPA) (Godbout and
Johnson 2009). Therefore, impaired immunoregulation of
both the periphery and CNS with age may predispose older
individuals to an increased frequency of peripheral infec-
tions associated with a myriad of neurological complica-
A. W. Corona
:
A. M. Fenn
:
J. P. Godbout
Department of Neuroscience, The Ohio State University,
333 W. 10th Ave,
Columbus, OH 43210, USA
J. P. Godbout
Institute for Behavioral Medicine Research,
The Ohio State University,
460 Medical Center Dr.,
Columbus, OH 43210, USA
J. P. Godbout
Center for Brain and Spinal Cord Repair,
The Ohio State University,
460 W. 12th Ave,
Columbus, OH 43210, USA
J. P. Godbout (*)
The Ohio State University,
259 IBMR Bld,
460 Medical Center Dr.,
Columbus, OH 43210, USA
e-mail: jonathan.godbout@osumc.edu
J Neuroimmune Pharmacol
DOI 10.1007/s11481-011-9313-4
tions. In support of this notion, normal aged individuals
(non-pathological) have an increased frequency of delirium,
depression, and cognitive decline concomitant with an
infection or illness (Jackson et al. 2004). Many of these
immune, cognitive, and behavioral defic its with infection
are recapitulated in rodent models of aging. The objective
of this review is to discuss peripheral and central immune
changes with normal aging that impinge on the coordinated
response between the immune system and the brain to
result in maladaptive behavioral and cognitive deficits.
A concept to introduce is the idea of successful aging
versus normal aging. One way to characterize success-
fully aged individual is by longevity. Moreover, researchers
have compared and contrasted various aspects of immunity
in centenarians (i.e., Individuals 100 years old and older) to
young adult, middle, and advanced age groups. Overall,
these studies indicate that there is a significant unilateral
deterioration of the immune system in the mid dle and
advanced age groups. Thus, in normal aging there is a
significant deterioration of immune function. While cen-
tenarians (100106 years) had a decline of lymphopoiesis,
it was not accompanied by a loss of immune function
(Sansoni et al. 1993, 2008). Moreover, the immune
responses of the centenarians were more comparable with
the group of young adults (1936 years) than to the groups
of middle and advanced aged adults. For example,
centenarians had remarkably conserved natural killer (NK)
cell activity and increased T-cell proliferation compared to
non-centenarian aged (6598 years) individuals. Along
with immune deficits in the middle and advanced aged
groups, there was an increased incidence of neurological
problems and cognitive decline. In contrast, cognitive
dysfunction and depression were rare in the centenarians
(Hausman et al. 2011). These data indicate that successful
aging is associated with a complex remodeling of the
immune system in the absence of significant loss of
function, whi le normal aging typically entails a progressive
loss of immune function. Furthermore, the decreased
incidence of behavioral and cognitive deficits in the
centenarians indicates a link between successful aging of
the immune system and maintenance of brain function.
Age-related changes in peripheral adaptive and innate
immunity
Peripheral adaptive immunity and aging
There are several key differences in adaptive immune
function with normal aging that influence immunity. One of
the hallmarks of aging in humans and rodent models is a
reduction in the numbe r of lymphocytes, particularly the
naïve T-cells. For example, in a study of healthy adults
ranging in age from 19 to 100 years old, healthy elderly
patients (7584 years old) had a reduced number of
circulating CD3
+
T-cells, including CD4
+
and CD8
+
T-cell
subsets, and reduced numbers of B-cells (Sansoni et al.
1993). A reduction i n lymphocytes is clinically relevant
because it is associated with reduction in antibody
production following vaccination (Grubeck-Loebenstein
et al. 2009) and with an impaired ability to clear viral and
bacterial infections (Toapanta and Ross 2009). More over,
these impairments in adaptive responses are associated
with a longer course of infection and illness in the aged
(Brunner et al. 2011).
Along with an age-associated reduction in the
number of lymphocytes the function of these cells may
be impaired with age or limited within the aged
microenvironment. For instance T-cells isolated from
aged mice have slower kinetics and decreased prolifer-
ation following stimulation with the T-cell mitogen
Concanaval in A (Con A) (Jiang et al. 2007). In addition,
clonal expansion of CD8
+
T-cells in aged mice was
reduced after exposure to influenza virus compared to
adults. This impairment was related specifically to the
microenvironment of the older animal. In support of this
idea, influenza specific T-cells isolated from adult mice
had slower and reduced proliferation when adoptively
transferred to aged mice (Jiang et al. 2009).
The reduction of T-cells w ith age is accompanied by
increase d marker s of T-cell activ ati on in memory T-cell
populations, including increased production of proin-
flammatory cytokines (Zanni et al. 2003). Increased
activation of memory T-cells in aged humans may be
caused by lifelong, chronic exposure to common viral
antigens such as h uman cytomegalovi rus (CMV) or
Epstein Barr virus (EBV). For example, aged T-cells from
patients infected with these viruses show enhanced
activation and proliferation when exposed to CMV or
EBV antigens (Vescovini et al. 2004). In aged mice
(18 month) t here was an abundant resident population of
CD8
+
T-cells in the spleen and lungs that expressed
markers of memory and enhanced antigen-independent
production of IFN-γ (Vesosky et al. 2006). Moreover, the
increase of this inflammatory memory CD8
+
T-cell
population was associated with increased early resistance
to Mycobacterium Tuberculosis. This, however, may not
be beneficial to the host organism. In the same model, the
early resistance to M. Tuberculosis infection in older mice
subsided by day 35 and there was an increased bacterial
load in older mice compared to young mice (Turner et al.
2002). These data are consistent with the notion of an
increased pro-inflammatory environment in aging that
resultsinimpairedclearingofinfectiouspathogens.
The humoral arm of the adaptive immune system is
mediated by B-cells. B-cells play an essential role in the
recognition and response to infectious agents. In
addition, impaired response to vaccines in the elderly
is underlied not only by impaired T-cell functions, but
by reduced specific antibody production by B-cells
(McElhaney 2009). Elderly humans show a reduction of
total B-cells with a decrease in the proportion of naïve B-
cells to antigen-experienced or exhausted B-cells, presum-
ably because of a life-time of antigenic load (Ademokun et
al. 2010). In a recent study, B-cell compartments from
normal aged individuals (6085 years old) were compared
with the aged offspring of centenarians (5683 year s old).
The children of centenarians had more abundant naïve B-
cells and did not show the same increase in exhausted
memory B-cells that characterized the normal aged
controls (Colonna-Romano et al. 2010). These dat a
indicate that success ful aging may be depend ent on
maintenance of a pool of naïve B-cells.
The underlying cause of age-related impairments in
adaptive immunity is unknown, but it may be associated
with altered hematopoietic stem cell populations (HSCs)
in the bone marrow. For example, results from a
microarray study indicate that there was decreased
expression of genes associated with lymphoid progenitor
cells and increased expression of myeloid progenitor
genes in the bone marrow of older mice compared to
adults (Rossi et al. 2005). Furthermore, the gene
expression profile of bone marrow progenitor cells was
maintained even when bone marrow from aged mice was
transplanted in to adults. These results are interpreted to
indicate that the changes to the gene profile are cell
autonomous. Moreover, there are distinct subsets of HSCs
that possess different capacities for self-renewal and
differentiation (Beerman et al. 2010 ). In this study, the
population of myeloid-biased cells was increased in aged
mice (Beerman et al. 2010). Taken together, these data
indicate that age-related changes i n the distribution of
adaptive immune cells are a consequence of hematopoietic
stem cell populations differences in the bone marrow.
Concomitant with reduced lymphocytes with age is
increased proliferation of cell populations that suppress
T-cell function. Two populations of cells that suppress
the adaptive immune system are T-regulatory cells (T-
regs, FoxP3
+
/CD25
+
/CD4
+
) ( Fontenot et al. 2003)and
myeloid derived suppressor cells (MDSCs). In older
humans (6287 years old) there was an increased number
of circulating T-regs that had an enhanced anti-proliferative
capacity compared to T-regs of adult mice (Rosenkranz
et al. 2007). In aged mice, there was increased expansion
of T-regs after i nfection with influenza that dose-
dependently suppressed T-cell proliferation (Williams-Bey et
al. 2011). MDSCs are a heterogeneous population of
immature myeloid cells that are characterized by the
expression of immune ma rkers including the intergrin
CD11b and Granulocyte differentiation antigen-1
(GR1). Subsets of MDSCs can be further differentiated
based on levels of Ly6C and Ly6G expression, which
are the two protein subcomponents of GR1. For
example , MDSCs can be divi d ed into two m ai n groups ,
granulocytic and monocytic MDSCs, that have different
mechanisms of T-cell suppression (Gabrilovich and
Nagaraj 2009 ). The majority of research on MDSCs has
been in the field of cancer etiology, however, recent
research is demonstrating changes in the MDSC popula-
tion with aging. Figure 1 (authors unpublished data)
shows an increased expansion of circulating MDSCs in
aged BALB/c mice compared to adult mice. In other
models, an altered M DSC populati on w ith age was shown
to contribute to age-related increases in cancer susceptibility.
In this study, MDSCs isolated from aged mice and trans-
planted into young mice was associated with increased tumor
susceptibility in young mice (Grizzle et al. 2007). The number
and activation of MDSCs was also increased during a
bacterial infection (Giordanengo et al. 2002;Gonietal.
2002) and during sepsis (Delano et al. 2007). Based on these
data, it is plausible that increases in suppressor cells in aging
contribute to impairments in adaptive immunity.
Peripheral innate immunity and aging
In addition to the impairments in the adaptive arm of
the immune system with age there are also significant
differences in innate immunity. This is relevant because
the innate immune system is the first defense against
viral and microbial pathogens. Examples include alterations in
the number and function of monocytes/macrophages, dendritic
cells, natural killer (NK) cells, NKT cells, and neutrophils with
aging (Shaw et al. 2010).
Related to the discussion above, the altered hematopoiesis
in aging is associated with an increase in myelopoiesis
at the expense of lymphopoiesis (Beerman et al. 2010).
Indeed, there are often increased numbers of innate
immune cells with age including monocytes, neutrophils,
and natural killer cells. In elderly humans, monocytes
increase with age and the number of monocytes was
correlated with increased frailty (Leng et al. 2009). Wh i le
the n umbers of myeloid cells are typically increased with
age, the functional responses are altered.
Neutrophils are responsible for killing rapid ly dividing
bacterial, yeast, and fungal infections. In rodent models of
aging, neutrophils exhibit an altered inflamm atory capacity
with reduced cytotoxic function. For example, in a burn
injury model there was no difference in neutrophil
accumulation in the lungs of aged mice and adult mice
after burn injury. In older mice, however, there was a
prolonged duration of inflammation and increased tissue
injury compared to adults (Nomellini et al. 2008). In
support of these findings, in older non-injured humans there
was also reduced chemotactic and microbicidal function of
neutrophils (MacGregor and Shalit 19 90; Wenisch et al.
2000). Altered neutrophil fu nction may be caused by
changes in lipid composition. For example, in older patients
with coronary artery disease, neutrophils have increased
production of reactive oxygen species, but have a lower
killing activity (Chan et al. 1998).
Macrophages are derived from blood monocytes and are
phagocytic cells capable of c learing pathogenic organ-
isms. In addition, macrophages present antigen on MHC
II and are potent mediators of innate inflammatory
responses. While the number of monocytes increase
with age, macrophages have a reduced inflammatory
capacity that may affect the clearance of pathogens. In a
murine model of Candida Albicans infection, purified
CD11b
+
peritoneal macrophages from aged (1820 month)
C57BL/6 mice had decreased production of proinflammatory
cytokines (IL-6, IL-1β, TNFα, and MIP-2), but similar
production of anti-inflammatory IL-10 compared to adults
(23 month). This inflammatory imbalance in the aged mice
was associated with reduced killing of the pathogen and
prolonged infection (Murciano et al. 2008). Moreover, this
same study showed a reduction of toll-like-receptor-2
(TLR2) expression on the peritoneal macrophages from
aged mice. Similar results were detected in other murine
models of infection. When aged mice were infected
with M. Tuberculosis, blocking the action of IL-10 during
chronic infection stabilized the bacterial load in the lungs
and improved survival in tuberculosis-susceptible CBA/J
mice (Beamer et al. 2008).
Other studies support a reduced innate function o f
peritoneal macrophages with age. In an importan t study,
aged and adult macrophages from mice were stimulated
with lipopolysaccharide ( LPS) ex vivo and gene expres-
sion was analyzed by microarray. LPS is a cell wall
component of gram-negative bacteria and a potent
activator of the innate immune system. Reduced
express ion of proin fla mm a tory cytokines and increased
expression of IL-10 after stimulation with LPS was
confirmed in the aged macrophages. Furthermore, genes
associated with toll-like receptor and NF-κβ signal ing
cascades were all reduced in the aged mice and genes
associated with the p38 mitogen-activated protein kinase
(MAPK) were increased (Chelvarajan et al. 2006).
Pretreatm e nt of the a ged macr op ha ges with low doses
of a p38 MAPK inhibitor (SB203580) prior to LPS
stimulation increased proinflammatory gene expression
and reduced IL-10 expression to levels comparable with
young L PS-treated macrophages (Chelvarajan et al.
2006). These results have important implications for
human studies. For instance, monocytes isolated from
10
0
10
1
10
2
10
3
10
4
10
0
10
1
10
2
10
3
10
4
GR1
Adult
10
0
10
1
10
2
10
3
10
4
10
0
10
1
10
2
10
3
10
4
Aged
Ly6C
% R1 (gMDSCs)
A.
0
10
20
30
40
B.
Adult Aged
C.
% R2 (mMDSCs)
*
1
2
0
*
Adult Aged
Fig. 1 I ncreased circulati ng
MDSCs in the blood of aged
mice. Adult (34 month) and
Aged (1822 month) mice were
sacrificed and blood was
collected by cardiac puncture.
To examine MDSC populations,
red blood cells were lysed and
blood cells were stained for
CD11b, GR1, and Ly6C and
analyzed by flow cytometry. a
Representative scatter plots for
Ly6C vs. GR1 staining are
shown for adult and aged mice.
R1 indicates gate for
granulocytic MDSCs (gMDSCs;
CD11b+/GR1hi/Ly6C+). R2
indicates gate for monocytic
MDSCs (mMDSCs; CD11b+/
GR1dim/Ly6C+). b Percentage
of gMDSCs. c Percentage of
mMDSCs. Bars represent the
mean ± SEM (n=10)
elderly humans have an impaired ability to kill cells from two
different tumor cell lines. The impaired function of the aged
monocytes was not reversed by various activation steps with
LPS or IFNγ stimulation (McLachlan et al. 1995).
NK cells are responsible for MHC-independent
cytotoxicity during a viral infection. The number of
NK cells does not change significantly with age, but the
cytotoxicity of each individual cell is decreased. In
support of this statement, a study of young and aged
humans discovered a reduction in the function of natural
killer cells in the 7584 year old age group (Sansoni et
al. 1993). Decreased cytotoxicity of the NK cells in
humans was associated with a decrease of chemokine and
cytokine production during NK cell activation (Ogata et
al. 1997). In addition, direct effects of NK cells on the
adaptive immune system were also detected with aging.
For example, in a study with aged BALB/c mice,
increased association of NK cells with B-cells in the bone
marrow led to reduced B-cell function (K ing e t al. 2009).
Reduced Z inc may unde rli e some of t he deficits i n N K
cells, as zinc is responsible for proper signali ng, and
supplementation of zinc in healthy elderly patients
restored some NK cell activity (Mariani et al. 2008).
Another type of NK cell that change with age are the
classical NKT cells. These are NK cells that express a T-cell
receptor and represent a rare class of innate immune
lymphocyte. In contrast with NK cells, numbers of NKT
cells are enhanced with age and show exaggerated function
after activation. Enhanced activation of NKT cells has been
shown to modulate the inflammatory environment of the
aged mouse. Notably, aged NKT cells were identified as
overproducers of IL-17 during a murine infection with
herpes simplex virus-2 (HSV-2) (Stout-Delgado et al.
2009). Over production of IL-17 is relevant, because
enhanced IL-17-dependent allogenic T-cell responses are
present in aged mice (Tesar et al. 2009). This has important
implications for hyper-inflammatory responses with age
during infection or sepsis.
Dendritic cells (DCs) are the professional antigen-
presenting cells and represent a link between the innate
and adaptive immune systems. In healthy aged human s,
enhanced production of IL-10 appears to in crease the
ability to present antigen to a T-cell culture line ex vivo
(Castle et al. 1999a, b). Other studies have found, however,
that DCs from aged humans have impaired chemotactic
capacity and ability to stimulate cytokine production from
influenza specific T-cells (Wick and Grubeck-Loebenstein
1997). In aged mice , reduc ed function o f DCs is a
contributing factor of age-related deficits in CD8
+
T-
cell expansion after influenza infection (Jiang et al. 2010).
In a similar study, the reduced ability of aged DCs to
stimulate T-cell responses was associated with reduced
MHC peptide complexes, reduced CD40 expression, and
reduced proinflammatory cytokine expression (Pereira et
al. 2011). These data indicate that impairments i n the
innate immune system can have profound effects for the
function of the adaptive immune system.
Taken together these data indicate there is red uced
adaptive immune function with normal aging. This involves
a reduction in T and B-cells, impaired antigen presentation,
and an increase in cells that suppress the immune system.
The changes of the innate immune system are variable and
complex. On one hand, certain subsets of innate immune
cells, like neutrophils, are more inflammatory when active.
While on the other hand, macr ophages and NK cells are
less inflammatory when activated. It is important to
highlight that increased inflammatory capacity does not
necessarily indicate that these cells have either increased or
decreased immune function. Overall, this creates an
imbalance in peripheral responses to pathogens that
contribute to the prolonged infectious episodes in the
elderly (See Table 1 for overview).
Age-related changes in the CNS immune system
The immune system of the CNS
Immunity in the CNS is mediated by resident microglia and
astrocytes and the various CNS-associated macrophages in
the choroid plexus, meninges, and the perivascular spaces
(Ransohoff and Perry 2009). Although T and B cells traffic
through the blood vessels and perivascular space, there is a
conspicuous lack of adaptive immune cells in the brain
parenchyma. The immune cells of the brain play a critical
role in the interpretation and propagation of inflammatory
signals in the brain. Mounting evidence indicates that
there is an increase in the inflammatory status of the
aged CNS. For example, increases in the inflammatory
profile of the resident glia are reported in several
models of aging including, rodents, dogs, nonhuman
primates, and humans. These impairments profoundly
affect re sponses to inflammatory stimuli and have
significant behavioral and cognitive consequences.
Moreover, the increased inflammatory profile of innate
immune cells in the brain argues for impaired immuno-
regulation with aging.
The resident microglia of the brain represent a unique
class of innate-immun e cell in the brain. Microglia are
derived from primitive yolk-sac macrophages that migrate
to the brain during early embryogenesi s (Alliot et al. 1999;
Ginhoux et al. 2010). The turnover of parenchymal micro-
glia from bone marrow is extremely limited (Carson et al.
2006). For example, in one study, microglia turnover from
bone marrow derived myeloid cells was very low over the
12 month period that the mice were examined (Ginhoux et
al. 2010). Other studies examining myeloid cell trafficking
in the context of CNS pathology indicate that self-renewal of
microglia is likely from a CNS derived progenitor source,
rather than from bone-marrow derived cells (Ajami et al.
2007; Mildner et al. 2007). This is in contrast with the CNS-
associated macrophages and other immune-cells in the
choroid plexus, perivascular space and meninges. These
cells are of bone-marrow derived origin and are expected to
be recycled from the periphery at a similar rate to other tissue
macrophages (Ransohoff and Perry 2009). The relative
stability of resident microglia in the brain may predispose
these cells to aging and inflammatory-related changes.
Evidence of altered microglial reactivity in the aged brain
Microglia are key mediators of the coordinated response to
infection by the peripheral immune system and CNS. These
cells respond to and propagate inflammatory signals
initiated at the periphery. In the absence of inflammatory
stimuli, microglia have a ramified morphology with small
cell bodies and many long and thin processes that are
constantly surveying their microenvironment (Davalos et
al. 2005; Nimmerjahn et al. 2005). Following activation,
microglia perform macrophage-like activities including
scavengi ng, phagocytosis , antigen p resentat ion, and
cytokine production (Hanisch and Kettenmann 2007).
Cytokines produced by activated microglia include IL-1β,
IL-6, and TNFα and are essential for induction and the
maintenance of sickness behavior (reviewed by, Dantzer
2001). These cytokine signals also trigger the release of
secondary inflammatory mediators including prostaglan-
dins and nitric oxide (Ericsson et al. 1997; Konsman et al.
1999; Marty et al. 2008). Activated microglia also produce
increased levels of anti-inflammatory cytokines, including
Table 1 Overview of age-related changes in periperhal adaptive and innate immune system
Cell Number Impairment Problem Model Selected
reference
Peripheral
Adaptive
Immune
System
Naïve T-cell Reduced expansion in
response to novel antigen
Reduced response to vaccinations
and impaired ability to fight
novel infections
Rodents Jiang et al. 2009
Memory T-cell Increased activation and
proinflammatory cytokine
production in memory
population
Increased baseline inflammation
and exaggerated response to
latent viral activation
Humans Zanni et al. 2003
T-reg (FoxP3+/
CD25+/CD4+)
Increased circulating
population of T-regs
that supress T-cell
proliferation
Dose-dependent suppression of
CD8+ T-cell response during
influenza infection
Rodents Williams-Bey
et al. 2011
B-cell Reduced antigen-specific
antibodies and increased
non-specific and
auto-antibodies
Limited repertoire of antibodies
and reduced response to
vaccinations
Humans Collana-Romano
et al. 2010
Peripheral Innate
Immune
System
Neutrophil Reduced chemotactic and
microbicidal function
Prolonged duration of inflammation
and increased tissue injury
during immune response
Rodents Nomellini
et al. 2008
Monocyte Increased inflammatory gene
profile following ex vivo
stimulation with LPS
Correlated with Increased frailty
with age along with increased
chronic systemic inflammation
Humans Leng et al. 2009
Macrophage Decreased production of
proinflammatory cytokines
with a maintenance or
increase of IL-10
Impaired killing of bacterial
pathogens with a prolonged
infection and increased morbidity
Rodents Murciano
et al. 2008
NK Cell Reduced chemokine and
cytokine production
Decreased cytotoxic capacity Rodents King et al. 2009
NKT Cell Increased function and
production of IL-17
Increased IL-17 dependent
T-cell response
Rodents Stout-Delgado
et al. 2009
Dendritic Cell Decreased functional antigen
presentation and decreased
proinflammatory cytokine
expression
Reduced ability to stimulate
T-cell response
Rodents Jiang et al. 2010
MDSC Decreased functional antigen
presentation and decreased
proinflammatory cytokine
expression
Suppression of T-cell
proliferation and function
Rodents (see Fig. 1)
Giordanengo
et al. 2002
IL-10, as a negative feed-back mechanism (Seo et al.
2004; Henry et a l. 2009). These neuroinflammatory
processes are norma lly transient, with microglia returning
to a resting state as the immune stimulus is resolved.
Microglia from the brain of aged gerbils (Choi et al.
2007)and dogs (Hwang et al. 2008) show a shift towards a
more activated morphology (thickened and deramified
processes) compared to young adults as deter mined by
Iba1 staining. These morphological changes correspond
with an increase in the expression of inflammatory markers
in the brain of normal aged rats (Perry et al. 1993), primates
(Sheffield and Berman 1998), and humans (Streit and
Sparks 1997; Kaunzner et al. 2010). Increased inflamma-
tory markers included major histocompatibility complex
(MHC) II (Perry et al. 1993; Ogura et al. 1994; Streit and
Sparks 1997; Sheffield and Berman 1998; Morgan et al.
1999; Nicolle et al. 2001; Streit et al. 2004; Godbout et al.
2005; Frank et al. 2006; Henry et al. 2008), scavenger
receptors (CD68) (Godbout et al. 2005; Wong et al. 2005),
CD11b and CD11c integrins (Perry et al. 1993; Stichel and
Luebbert 2007), and toll-like-receptors (TLRs) (Letiembre
et al. 2007). The number of resident microglia, however,
are not generally increased in the brain with age (Long et
al. 1998; Morgan et al. 1999); though one study did find a
slight increase of microglia in the brain of aged female, but
not male, mice (Mouton et al. 2002). These data indicate
that increased inflammatory markers are mostly occurring
on existing microglia populations.
Collectively, these changes are termed microglial
priming. This terminology reflects the original finding
that peripheral macrophage that were primed by
application of interferon-γ had more robust responses
to subsequent LPS stimulation (Johnson et al. 1983;
Pace et al. 1983). The presence of this priming effect in
microglia of the CNS was first demonstrated in a mouse model
of neurodegeneration using prion disease (Cunningham et al.
2005) and has subsequently been demonstrated in normal
aging. A functional consequence of microglial priming in
aging and other models is an exaggerated neuroinflammatory
response during a peripheral or central immune activation
(Godbout and Johnson 2006; Perry et al.
2007; Dilger and
Johnson 2008; Henry et al. 2009; Jurgens and Johnson 2010).
In support of this notion, mixed glial cultures and coronal
brain sections derived from aged mouse brains were
hyper-responsive to LPS stimulation and produced more
IL-1β andIL-6comparedtoculturesestablishedfrom
adult brains (Ye and Johnson 2001; Xie et al. 2003).
Furthermore, ex vivo cultured microglia from the brain of
aged mice constitutively expressed increased IL-6 and
TNFα levels compared to microglia from young adults
(Njie et al. 2010). In vivo studies show that stimulation of
the peripheral innate immune system by injection of
lipopolysaccharide (LPS) caused a prolonged and exaggerated
neuroinflammatory cytokine response (IL-1β and IL-6) in
aged (2224 month) BALB/c mice compared to young adults
(Godbout et al. 2005). Similarly, peripheral injection of
Escherichia coli (E. coli) promoted higher and prolonged
levels of IL-1β in the hippocampus of aged rats compared to
young adults (Barrientos et al. 2006, 2009a).
It is important to mention that while a peripheral
injection of LPS or E. coli caused higher levels of IL-1β
in the brain of aged rodents compared to young adults,
plasma levels of IL-1β were not amplified (Godbout et al.
2005; Barrientos et al. 2006, 2009a). The disconnection
between peripheral IL-1β induction and brain IL-1β has
been interpreted to suggest that an amplification of the
immune response occurs within the brain specifically.
Indeed, central activation of the innat e immune system by
intracerebroventricular (i.c.v.) administration of LPS or
GP120 caused amplified mRNA expression of inflammatory
cytokines, IL-1β,IL-6,andTNFα in aged (2224 month)
mice (Abraham et al. 2008; Huang et al. 2008). These studies
provide evidence that increased proinflammatory cytokine
production in the aged brain is not entirely dependent on an
altered peripheral immune system and can be attributed to a
reactive glial population.
Much of this exaggerated cytokine production can
now be attributed specifically to hyperactivated micro-
glia. For instance, ex vivo stimulation of microglia from
aged mice with LPS (Frank et al. 2010) or Pam3CSK4, a
TLR2 agonist (Nji e et al. 2010), result ed in exaggerated
production of I L-1β,IL-6,andTNFα
. compared to adult
controls. When microglia were isolated from whole brain
homogenates after a peripheral LPS injection, microglia-
specific mRNA levels of TLR2, IDO, and IL-1β were
increasedinagedcomparedtoadultmice(Henryetal.
2009). It is important to note that aged microglial reactivity is
not limited to increased production of pro-inflammatory
cytokines, but anti-inflammatory cytokines as well, such as
IL-10. For example, aged mice had amplified microglial
specific mRNA induction and intracellular protein expression
of both IL-1β and IL-10 compared with adult mice following
LPS injection (Sierra et al. 2007; Henry et al. 2009).
Furthermore, a key point shown by Henry et al. was that
the reactive (MHC II
+
) microglia of aged mice had the
most prominent IL-1β induction following immune
challenge compared to non-reactive (MHC II
-
) microglia.
These studies indicate that after a peripheral immune
stimulus, aged mice show hyperactivation of primed,
MHC II
+
microglia with exaggerated and prolonged
production of inflammatory cytokines.
Impaired immunoregulation in the aged brain
Evidence of an enhanced inflammatory profile of the brain
combined with a prolonged and exaggerated neuroimmune
response indicates that there are significant changes to
immunoregulation in the aged brain. These changes
result in what we refer to as a primed or reactive
microglial population. It is important to highl ight that
other groups describe the aging microglial population as
senescent or dystrophic (Streit and Xue 2009). The
terminology used depends on the context in which the
microglia are examined. Microglia of aged rodents
produce more inflammatory cytokines following activation,
indicating increased priming and reactivity. Microglia from
older rodents also have functional impairments. For
example, there was reduced phagocytosis of beta-amyloid by
microglia from older AD transgenic mice (Hickman et al.
2008; Lee et al. 2010). Aged microglia also respond more
slowly to a retinal injury and display a prolonged
aggregation at the injury site compared with adult mice
(Damani et al. 2011). These functional impairments may
be considered indicators of microglial senescence. Based
on the literature presented, increased reactivity of microglia
does not necessarily translate into increased innate immune
function. In addition, senescence does not indicate that aged
microglia are incapable of any type of immune response. The
terminology of microglial priming or microglial senescence
are not mutually incompatible and both reflect age-related
changes in immunoregulation.
Studies with minocycline, a tetracycline antibiotic and anti-
inflammatory agent with microglial-inhibitory properties
(Nikodemova et al. 2007), support the notion that impaired
immunoregulation of microglial activation is an important
contributor to age-associated neuroinflammation. For exam-
ple, in aged rats minocycline reduced expression of MHC II
and CD86 and attenuated the age-related impairments in
long-term potentiation (Griffin et al. 2006). Moreover,
minocycline pretreatment in aged BALB/c mice normalized
the LPS-induced exaggeration in mRNA expression of
neuroinflammatory markers including IL-1β and TLR2
(Henry et al. 2008). These data support the hypothesis that
reactive microglia play an important role in exaggerated
neuroinflammation in the aged brain following innate
immune activation. Minocycline is an inhibitor of not
only microglial activation, but also alters that activity of
peripheral macrophages (Amin et al. 1997; Attur et al.
1999). Because minocycline is not specific for microglia,
it is difficult to interpret how it mediates these anti-
inflammatory effects. More recent studies have identified
specific immunoregulatory pathways and interactions that
become impaired with age.
Impaired neural regulation of microglia with age
CD200 is a member of the immunoglobulin superfamily
and is con stitutively expressed on the surface of neurons.
The corresponding CD200 receptor (CD200R) is expressed
on microglia (Hoek et al. 2000; Lyons et al. 2007). CD200-
CD200R signaling is involved with keeping microglia in a
quiescent state (Hoek et al. 2000). For example, peripheral
injection of LPS caused a significant decrease of CD200R
on microglia 4 h after injection, along with an increase of
microglial activation (Masocha 2009). This is relevant
because there is reduced expression of CD200R on the
surface of microglia from aged rats compared with adults
and this reduction is associated with increased MHC II
expression (Lyons et al. 2007). These data are consistent
with those from a previous study showing that levels of
CD200R mRNA were lower in the brain of older rats
(Frank et al. 2006). Recent studies indicate t hat the
reduction of CD200R on aged microglia may be caused
by reduced anti-inflammatory mechanisms. For example,
subcutaneous injection of a mimetic of the neural cell
adhesion molecule (NCAM) enhanced CD200 expression
in aged mice, reduced the age-related increase in CD86, and
attenuated expres sion of pro-inflammatory cytokines in the
brain following LPS injection (Downer et al. 2010).
Another neuronal regulator of microglia, the chemokine
fractalkine (CX
3
CL1), also plays a role in age-related
microglial dysregulation. Fractalkine signaling to the
fractalkine receptor (CX
3
CR1) on microglia reduces pro-
duction of proinflammatory cytokines in cultured microglia
(Zujovic et al. 2000). In vivo, CX
3
CR1-deficient mice
(CX
3
CR1
/
mice) exhibited enhanced microglial activation
after repeated intraperitoneal LPS injection. Exaggerated
microglia activation was also associated with increased
microglial-mediated neurotoxicity (Cardona et al. 2006).
Recent studies show that there is an age-related reduction of
CX
3
CL1 protein in the brain of ag ed mice (Wynne et al.
2010) and rats (Bachst etter et al. 2009; Lyons et al. 2009a).
Infusion of recombinant CX
3
CL1 into the brain of aged rats
reduced microglial MHC II expression, indicating a
decrease in primed microglia (Bachstetter et al. 2009).
Infusion of CX
3
CL1 also restored age-related deficits in
PI3K/Akt activation i n the aged rat hippocampus, an
important surviva l pa thway thought to be involved in
maintaining microglial quiescence (Lyons et al. 2009a ).
Moreover, recent studies show that the surface expression
of CX
3
CR1 is dysregulated on microglia during neuro-
immune responses in aged BALB/c mice (Wynne et al.
2010). In this study, flow cytometric analysis of isolated
microglia revealed that the expression of CX
3
CR1 on the
surface of microglia was significantly reduced 4 h after an
injection of LPS. While young mice recovered expression
of CX
3
CR1 by 24 h after the injection, aged mice showed a
prolonged downregulation of the re ceptor with no
significant recovery. This study indicates that functional
fractalkine signaling is i mpaired f or an extended amount
of time after an immune stimulus and may contribute to
prolonged microglial activation in the aged brain.
Indeed, adult CX
3
CR1
/
mice also show deficits in the
resolution of microglial activation after an LPS injection
compared with heterozygote littermates (Corona et al. 2010).
Impaired anti-inflammatory feedback in the aged brain
The exaggerated neuroimmune response with age may
be caused by impaired anti-inflammatory feedback to
shut-off the immune re sponse. For example, anti-
inflammatory cytokines involved with the resolution of
inflammatory signals in the brain including IL-10, TGFβ,
IL-4, and IL-1RA (Shull et al. 1992;Blutheetal.1999;
Heyen et al. 2000), are proposed to be dysregulated with age.
For example, reports of reduced levels of IL-10 in mixed
glial cultures and brain sections of aged mice compared to
adult controls are mirrored by an increase in inflammatory,
IL-6 expression (Ye and Johnson 2001). These may not be
microglial specific, however, as separate studies have
reported an increase in microglia IL-10 production in aged
mice following an immune stimulation (Sierra et al. 2007;
Henry et al. 2009). Alternatively, microglia could also
exhibit decreased sensitivity to anti-inflammatory cytokines.
In other studies, reduced levels of IL-4 in the brain of aged
rats corresponded to an increase in IL-1β and MHC II
expression (Nolan et al. 2005). Furthermore, an age-related
decrease of IL-4 in the brain may contribute to reduced
CD200 expression in neurons (Lyons et al. 2009b). These
inflammatory exaggerations were reversed when IL-4 was
infused into the brain. Although glial cells of the central
nervous system produce IL-4 in vitro (Nolan et al. 2005), IL-
4 is classically produced by adaptive immune cells in the
periphery. Thus, the origin of IL-4 production in the brain is
controversial. Recent studies indicate that T-cells circulating
the meningeal spaces of the brain may be a source of IL-4 in
the brain (Derecki et al. 2010). In addition to IL-4, reduced
expression of the anti-inflammatory cytokine, TGFβ,inthe
aged brain may underlie impaired upregulation of CX
3
CR1
on microglia following LPS stimulation (Chen et al. 2002)as
mentioned previously (Wynne et al. 2010).
Other anti-inflammatory pathways, including gluco-
corticoids, catecholamines and n eurotransmitters, may
also be impaired in the aged brain leading to abrogated
attenuation of neuroinflammation ( Dello Russo et al.
2004; Glezer and Rivest 2004). For instance, recent
studies indicate that there is decreased glucocorticoid
receptor expression on astrocytes in the hippocampus of
older rats ( Kasckow et al. 2009). These defi cits may be
associated with impaired negative feedback of glucocorticoids
in the aged brain (Mizoguchi et al. 2009). Furthermore,
GABA, an inhibitory neurotransmitter, can attenuate
microglial specific IL-1β production through interactions
with microglial GABA
B
receptors (Kuhn et al. 2004). Studies
show reduced expression of GABA-ergic internerons within
the hippocampus of aged mice associated with increased
mRNA expression of IL-1β and TNFα (Gavilan et al.
2007). Microglial activation is also modulated by neuro-
peptides including endogenous cannabinoid (CB), ananda-
mide. CB receptors are present on microglia (Cabral and
Marciano-Cabral 2005) and stimulation of CB1/2 receptors
with the selective agonist, WIN-55212-2, reduced the number
MHC II
+
microglia in aged rats (Marchalant et al. 2008).
Collectively, these data show that impaired immunoregulation
by anti-inflammatory mediators in the aged brain may
underlie the enhanced neuroimmune response.
Behavioral and cognitive consequences of impaired
coordination between the immune system and the brain
Sickness and depressive-complications following innate
immune challenges
Impaired immunoregulation of microglia leads to an
amplified neuroinflammatory response that corresponds
to behavioral deficits (Table 2). One potential conse-
quence of an imbalanced coordinated response between
the immune system and the brain is the i nduction of
prolonged sickness and depressive-like behaviors. While
the inducti on of cytokine-mediated sickness behavior is a
necessary and beneficial response to systemic infection, an
amplified or prolonged response affects behavioral and
cognitive processes (Jurgens and Johnson 2010). In the
studies discussed above, peripheral or central immune
stimulation with LPS caused protracted neuroinflamma-
tion in the brain of aged rodents. This w as paralleled b y a
prolonged sickness r esponse with protracted anorexia,
lethargy, and social withdrawal (Godbout et al. 2005;
Abraham et al. 2008;Huangetal.2008). An amplified
sickness response was also detected in older rats that were
infected subcutaneously with E. coli. The aged rats
displayed an altered febrile response including a blunted
and delayed increase of core body temperature followed
by a significant and prolonged increase (Barrientos et al.
2009b). Extended sickness behaviors in aged BALB/c
mice were likely driven by exaggerated microglial I L-1β
(Henry et al. 2009). In support of this notion, i.c.v.
infusion of IL-1 receptor antagonist (IL-1RA) reversed the
prolonged LPS-induced sickness behavior in aged mice
(Abraham and Johnson 2009a).
Related to prolonged sickness behavior, there is also
evidence of development of depressive-like complications
in aged rodents following an immune challenge.
Depressive-like complications in rodent models are
reflected by increased resignation behavior (i.e. immobi lity)
in the forced swim test, or tail suspension test. These
behavioral assays are intended to model the aspect of
despair displayed by depressed human patients (Cryan et al.
2005). In aged BALB/c mice, peripheral stimulation of the
innate immune system with LPS caused prolonged
depressive-like behavior 72 h after injection in aged mice
(Godbout et al. 2008). In this study aged mice showed
increased resignation behavior in the forced-swim and tail-
suspension tests even after the acute effects of LPS on lethargy
and food intake were resolved. These protracted depressive-
like behaviors are likely a direct consequence of the impaired
regulatory mechanisms of microglia. As mentioned previous-
ly, microglia from aged BALB/c mice show extended down
regulation of CX
3
CR1 on microglia that may be an
underlying cause of prolonged microglial activation (Corona
et al. 2010; Wynne et al. 2010). Consistent with this finding,
adult CX
3
CR1-deficient mice displayed prolonged social
withdrawal and depressive-like behaviors 48 and 72 h after
an LPS injection. The depressive-like behavior in CX
3
CR1-
deficient mice was paralleled by a prolonged activated
morphology of microglia in the absence of apparent neuronal
death (Corona et al. 2010).
The underlying cause of the transition from sickness
to prolonged depression is unclear, though a strong
association exists between prolonged inflammation and
induction of depression in humans and rodents (Raison
et al. 2006; D antzer et al. 2008). Indoleamine-2,3-
dioxygenase (IDO) production and activity is induced at
high levels in the periphery and CNS following an innate
immune challenge. It is hypothesized that I DO activation
in microglia and macrophages by inflammatory cytokines
(i.e. IL-1β,TNFα,IFNγ) is a key mechanism underlying
mood and d epressive complications because it alters
serotonergic, dopaminergic, and noradrenergic neuro-
transmission (Rai son et al. 2006; Muller and Schwarz
2007; Poeggeler et al. 2007; Dantzer et al. 2008). Active
IDO converts tryptophan (TRP) into kynurenine (L-KYN)
whichisthenprocessedintoneuroactivemediators,
including 3hydroxy-kynurenine (3HK) and quinolinic
acid (QUIN) (Stone and Darli ngton 2002). Work by
OConnor et al. showed that inhibition of IDO by 1-
methyl try ptophan (1-MT) inhibited acute depression
Table 2 Overview of behavioral and cognitive consequences of age-related impairments in immuno-regulation
Impairment Consequence Model Reference
Sickness
Behavior
Primed microglial population is
hyper-reactive to peripheral or
central LPS injection
Prolonged sickness behavior syndrome
following immune challenge (i.e.
anorexia, lethargy, social withdrawal)
Mice Godbout et al. 2005;
Huang et al. 2008
Primed microglial population is
hyper-reactive to peripheral
E. coli infection
Altered febrile response. Blunted and
delayed induction of fever followed
by a sustained increase
Rats Barrientos
et al. 2009a, b
Increased induction of proinflammatory
cytokines such as IL-1β following LPS
LPS-induced sickness behavior in
aged mice was blocked by i.c.v.
infusion of IL-1RA
Mice Abraham et al. 2008
Depressive
Behavior
Primed microglial population is
hyper-reactive to peripheral or
central LPS injection
Development of prolonged depressive-
like behavior (i.e. increased immobility
in the forced swim or tail-suspension test)
Mice Godbout et al. 2008
Prolonged impairment in fractalkine-
mediated regulation of microglia
Development of prolonged depressive-
like behavior following LPS injection
paralleled by increased activated
morphology of microglia
Mice Wynne et al. 2010;
Corona et al. 2010
Prolonged induction of IDO activity Development of depressive-like behavior
was blocked by blockade of IDO with 1-MT
Mice OConnor et al. 2009
Cognitive
Deficits
Primed microglial population is
hyper-reactive to peripheral
E. coli infection
Impaired hippocampal-dependent
context fear conditioning and spatial
memory following immune challenge
Rats Barrientos
et al. 2006, 2009b
Increased oxidative stress Resveratrol, a potent anti-oxidant,
attenuated working memory deficits
and neuroinflammation after LPS injection
Mice Abraham and
Johnson 2009b
Altered
Neuro-Plasticity
Reduced neurogenesis and
dendritic atrophy following
an LPS injection
Possible underlying factor of prolonged
cognitive and depressive-like behavior
Mice Richwine et al. 2008
Impaired long-term potentiation
following E. coli infection mediated
by increased IL-1β induction
Impaired memory consolidation and
reduced Arc expression following
recovery from E. coli infection was
blocked by i.c.v. infusion of IL-1RA
Rats Chapman et al. 2010;
Frank et al.
2010
Reduced sensitivity to anti-
inflammatory feedback
(i.e. cannabinoid mediation)
Stimulation of cannabinoid receptors
reduced microglial activation
and memory deficits
Rats Marchalant et al. 2008
associated with LPS injection in adult m ice (OConnor et
al. 20 09 ). Furthermore, injection of LPS caused prolonged
expression and activity of IDO in the aged brain (Godbout
et al. 2008). The increased induction of microglia-specific
IDO mRNA in aged microglia compared to young adults
following LPS could be prevented by pretreatment with
minocycline (Henry et al. 2009). Last, LPS-induced
amplification of KMO and IDO mRNA levels were
detected in microglia of CX
3
CR1
/
compared to controls
(Corona et al. 2010). Moreover, the prolonged depressive
behavior in CX
3
CR1
/
mice was blocked by 1-MT
pretreatment (unpublished data, Cor ona et al.). T hus,
failure to tightly regulat e microglial activation in the brain
may lead to significant and prolonged activation of the
IDO pathway and subsequent depressive complications.
Cognitive complications following innate immune
challenges
Increased cytokine production in the aged brain after
peripheral innate immune challenge is also associated with
impaired cognitive function. For example, injection of LPS
caused an amplified cytokine response in the hippocampus
of older mice that was paralleled by impaired hippocampal-
dependent spatial memory (Chen et al. 2008). Moreover,
infection by E. coli led to prolonged production of IL-1β in
the hippocampus of aged rats (Barrientos et al. 2009a) and
reduced long-term contextual memory examined by
context-dependent fear conditioning and Morris water maze
(Barrientos et al. 2006, 2009a). When aged mice were fed a
diet supplemented with resveratrol, a potent anti-oxidant,
LPS-induced neuroinflammation and working memory
deficits were attenuated (Abraham and Johnson 2009b). It
is important to highlight that in the absence of an immune
stimulus, there is not a significant effect of age on the
acquisition of memory tasks. There is, however, evidence
of age-associated memory problems in the reversal task of
the Morris water maze (Jang et al. 2010). Nonetheless, age-
related cognitive impairment is profoundly exaggerated
when a secondary immune stimulus is provided.
Age-related alterations of neuroplasticity follow ing innate
immune challenges
The mechanisms by which age-related neuroinflammation
causes depressive-like and cognitive complications are
unclear, but a potential explanation is that neuroinflamma-
tory pathways can impa ct neuronal plasticity (e.g., neuro-
genesis, long-term potentiation, and dendritic restructuring).
For example, when neuroinflammation was prolonged in
aged mice, increased dendritic atrophy was detected in the
CA1 region of the hippocampus (Richwine et al. 2008). In
addition, neurogenesis steadily decreases throughout life in
mouse models of aging (Ben Abdallah et al. 2010 ) and may
be further disrupted by inflammation (Ekdahl et al. 2003;
Monje et al. 2003). It is expected that age-related decreases
in neurogenesis would be exaggerated during an inflam-
matory challenge, but to our knowledge, this has not been
directly studied. Nevertheless, it is possible that impaired
microglial regulatory processes in the aged brain would
negatively impact neurogenesis. For example, Bachstetter
et al. have shown that CX
3
CR1-deficient mice show
profound deficits in neurogenesis. Infusion of recombinant
CX
3
CL1 into the brain of the aged rats reversed this
decrease (Bachstetter et al. 2009). Therefore, it is plausible
that a prolonged impairment of CX
3
CR1 on the microglia
of aged mice after an LPS injection (Corona et al. 2010)
may cause to impaired neuroplasticity, leading to depressive-
like and cognitive complications.
Increased pro-inflammatory cytokines and other neuro-
inflammatory pathways also suppress long term potentia-
tion (LTP) (Murray and Lynch 1998; Vereker et al. 2000;
Kelly et al. 2001; Griffin et al. 2006). LTP is a key
mechanism involved in memory formation and can have
differen t manifestations, including early and late-phase
LTP. A recent study exami ned different types of LTP in
hippocampal slices prepared from young or aged rats after
recovery from E. coli infection or no infection. Early-phase
LTP was not different with age, but late-phase LTP was
significantly suppressed in aged rats 4 days after E. coli
infection in hippocampal area CA1 (Chapman et al. 2010).
These electophysiological data correspond with observed
deficits in long-term memory with age. Suppression of LTP
is likely caused by enhanced IL-1β expression as i.c.v.
administration of IL-1RA reversed the E .coli induced
suppression of late-phase LTP in aged rats (Chapman et al.
2010). Furthermore, IL-1RA also prevented E. coli-
induced suppression of Arc expression, an immediate early
gene that is essential for LTP, and long term memory
consolidation in contextual fear conditioning in aged rats
(Frank et al. 2010). Other anti-inflammatory pathways had
similar effects as IL-1RA on cognitive recovery. For
example, stimulation of CB1/2 receptors with the selective
agonist, WIN-55212-2, reduced microglial activation and
memory deficits in aged rats (Marchalant et al. 2008).
Taken together, these data show that impaired regulation of
the neuroimmune response results in inflammatory
cytokine-mediated suppression of neuronal plasticity to
cause cognitive deficits.
Does an age-related change in peripheral immunity
have a direct influence on cognition?
Recent studies report that circulating T-cells actively
support cognition. For instance, there were profound
impairments in hippocampal-dependent spatial learning
and memory in mice deficient in T-cells (severe combined
immune deficiency (SCID) mice ) (Kipnis et al. 2004;
Brynskikh et al. 2008). Moreover, wild type mice depleted
of T-cells with administration of anti-CD3 antibodies
also had impaired performance in reversal training in
the M orris water maze. Reconstitut ion with wild-type T-
cells reversed the learning deficits detected in the
immune-compromised mice (Brynskikh et al. 2008;Wolf
et al. 2009). Furthermore, the effects were specific for
CD4
+
T-cells, because replenishment with CD8
+
T-cells
alone did not attenuate the learning deficits (Wolf et a l.
2009). In addition, interleukin-(IL)-4 production by T-cells
within the meninges is proposed to support neurogenesis
(Derecki et al. 2010). The IL-4 produced by T-cells in the
meninges may affect cognition by shifting the activation
state of meningeal macrophages. This idea is supported by a
recent study where macrophages that were stimulated with
IL-4 ex vivo and then transplanted into mice could enhance
cognition in immune-compromised mice, even in the
absence of T-cells (Derecki et al. 2011). A logical extension
of these studies is that reduced numbers and impaired
function of the adaptive immune system with normal
aging may contribute to age-dependent deficits in
cognitive function. In support of this notion, one study
has demonstrated that lethal radiation of aged mice
followed by bone marrow transplants from congenic
mice reversed deficits in novel location recognition
(Ron-Harel et al. 2008). The precise mech anism by
which trafficking of peripheral immune cells support
normal neurogenesis and contribute to cognitive function
is unknown, but these findings indicate that age-associated
alterations of the peripheral immune system with an
increased inflammatory profile may have a direct and
negative affect on cognition.
Studies in human populations reveal a link between
depressive and cognitive c omplications and altered
peripheral immune function. As discussed earlier, life-
long exposure to common viral infections l ike CMV is
associated with exaggerated inflammatory responses,
increased memory T-cells, and reduced naive CD4
+
T-
cells. A recent study demonstrated that elderly people with
the lowest cognitive function and highest rates of
depression had markedly enhanced T-cell activation in
response to CMV antigens (Vescovini et al. 2010). Related
to this finding, elderly patients with the lowest vaccine
response and most increased susceptibility to viral and
bacterial insults also had the hi ghest inc idence of
depression (Gouin et al. 2008). In addition, there is an
increased prevalence of long-term cognitive deficits in
elderly patients after a surgery, such a s major cardiac or
orthopedic surgery (Ancelin et al. 2010). These fi ndings
demonstrate a correlation between impaired peripheral
innate and adaptive immunity age-related cognitive defi-
cits. Although recent animal studies indicate that a direct
effect is possible, continued research is necessary to determine
the mechanisms by which age-related peripheral immune
changes may be directly causing the cognitive defects.
Conclusion
There is significant reorganization of the immune system in
normal aging. Impaired immunoregulation is apparent in
both the peripheral innate and adaptive immune system and
in the immune system of the CNS. Communication
between the peripheral and CNS immune systems is
essential for the coordinated responses of the immune
system. This review highlights the prolonged behavioral
and cognitive complications that are associated with
impaired immunoregulation. It is important to note that
increased mic roglia priming and reactivity are detected in a
variety of rodent models of stress and disease. For example,
altered glial populations and behavioral and cognitive
impairment is observed in rodent models of early life
infection (Bilbo and Schwarz 2009), CNS neurological
disease (Perry et al. 2007), and repeated social defeat
(Wohleb et al. 2011 ). Although outside the scope of this
review, these models of stress and disease are often
exacerbated by increasing age and represent an intriguing
area of research that deals with the overlap of the immune
system with disease.
It is important to highlight that the immune system does
not operate in isolation and is profoundly influenced by
hormones, the HPA axis, endothelial cells, and other
components that are highly variable with age (Biber et al.
2007; Ransohoff and Perry 2009). Thus, it is often difficult
to determine if impaired immunoregulation is a result of
intrinsic immune changes, or changes mediated by non-
immune components of aging. These inconsistencies often
lead to apparent conflicts between the hypotheses of
immunosenescence and Inflamm-aging. For example,
aged humans show chronic low grade levels of inflamma-
tory markers in the plasma, including IL-6, acute-phase
proteins, and C-reactive prote in, that are predictive of a
range of inflammatory diseases like atherosclerosis (Libby
2006), Type-2 diabetes (Festa et al. 2002a, b), and
neurodegener ative d iseases (Griffin 2006). Thi s is in
contrast to the behavior of many peripheral innate immune
cells that have decreased function, reduced pro-inflammatory,
and increa sed anti-inflammatory cytokine production in
response to an immune challenge. The intrinsic changes in
the aged immune system likely have a complex interaction
with the aged environment that is not fully understood.
A large body of literature supports the hypothesis that a
dysregulated immune response in the aged brain is an
underlying cause of behavioral and cognitive difficulties
with aging. Less is known, however, about the relative
contribution of the peripheral immune system in this
phenomenon. Impaired immunoregulation of the peripheral
immune syst em is also correlated with altered cognitive
function in the elderly. Impaired regulation of the peripheral
immune system likely contributes to an inflammatory
environment that is permissive to long-term changes in
the inflammatory state of the brain. Furthermore, impaired
response to microbial and viral pathogens increases the
susceptibility to infections in aged rodents and human s.
This may increase neuroinflammation indirectly by increas-
ing the incidence and severity of peripheral infections.
Notably, recent animal studies have identified a possible
direct interaction of peripheral immune cells with the brain
through meningeal immunity, but the mechanisms by which
this occurs remain mysterious. Further research is necessary
to elucidate the role of the multiple age-related changes in
peripheral immune system on the regulation of behavioral
and cognitive function in the elderly. In conclusion, an
integrated approach to the immune system that takes into
account the changes to both the peripheral and CNS
immune system will be highly valuable to move forward
in this line of research.
Conflict of interest The authors declare no actual or potential
conflicts of interest.
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    • "A hallmark of the aged brain is impaired immunoregulation and neurogenesis, associated with a decline in the neurological function (Aguiar et al., 2011; Corona et al., 2012; Erickson et al., Figueiredo et al., 2010). Here, 21–23 month-old aged mice demonstrated this impaired phenotype. "
    [Show abstract] [Hide abstract] ABSTRACT: Exercise improves mental health and synaptic function in the aged brain. However, the molecular mechanisms involved in exercise-induced healthy brain aging are not well understood. Evidence supports the role of neurogenesis and neuroplasticity in exercise-induced neuroplasticity. The gene silencing transcription factor neuronal RE1-silencing transcription factor (REST)/neuron-restrictive silencer factor (NRSF) and an anti-inflammatory role of exercise are also candidate mechanisms. We evaluate the effect of 8 weeks of physical activity on running wheels (RW) on motor and depressive-like behavior and hippocampal gene expression of brain-derived neurotrophic factor (BDNF), REST, and interleukins IL-1β and IL-10 of adult and aged C57BL/6 mice. The aged animals exhibited impaired motor function and a depressive-like behavior: decreased mobility in the RW and open field and severe immobility in the tail suspension test. The gene expression of REST, IL-1β, and IL-10 was increased in the hippocampus of aged mice. Physical activity was anxiolytic and antidepressant and improved motor behavior in aged animals. Physical activity also boosted BDNF and REST expression and decreased IL-1β and IL-10 expression in the hippocampus of aged animals. These results support the beneficial role of REST in the aged brain, which can be further enhanced by regular physical activity.
    Full-text · Article · Jul 2016
    • "In general, microglia activation and the increased expression of cytokines are aimed to be protective to the CNS and beneficial to the host organism. This is represented in their role in mediating the behavioral symptoms of sickness following innate immune challenge (Corona et al., 2012). Moreover, a recent study shows that repeated injection of lipopolysaccharide (LPS) moves microglia towards a novel profile in which they migrate to the synapses of inhibitory neurons displacing them from cortical neurons (Chen et al., 2014). "
    [Show abstract] [Hide abstract] ABSTRACT: Glia of the central nervous system (CNS) help to maintain homeostasis in the brain and support efficient neuronal function. Microglia are innate immune cells of the brain that mediate responses to pathogens and injury. They have key roles in phagocytic clearing, surveying the local microenvironment and propagating inflammatory signals. An interruption in homeostasis induces a cascade of conserved adaptive responses in glia. This response involves biochemical, physiological and morphological changes and is associated with the production of cytokines and secondary mediators that influence synaptic plasticity, cognition and behavior. This reorganization of host priorities represents a beneficial response that is normally adaptive but may become maladaptive when the profile of microglia is compromised. For instance, microglia can develop a primed or pro-inflammatory mRNA, protein and morphological profile with aging, traumatic brain injury and neurodegenerative disease. As a result, primed microglia exhibit an exaggerated inflammatory response to secondary and sub-threshold challenges. Consequences of exaggerated inflammatory responses by microglia include the development of cognitive deficits, impaired synaptic plasticity and accelerated neurodegeneration. Moreover, impairments in regulatory systems in these circumstances may make microglia more resistant to negative feedback and important functions of glia can become compromised and dysfunctional. Overall, the purpose of this review is to discuss key concepts of microglial priming and immune-reactivity in the context of aging, traumatic CNS injury and neurodegenerative disease. Copyright © 2014. Published by Elsevier Ltd.
    Full-text · Article · Nov 2014
    • "While we have not observed overt neuronal injury in the brains of mice that have experienced TETS-induced seizures, we have consistently observed delayed neuro-inflammation, evident as reactive astrogliosis and microglial activation (Vito et al., in press; Zolkowska et al., 2012). Behavioral deficits and cognitive decline are associated with neuroinflammation (Corona et al., 2012; Dantzer et al., 2008; Maes et al., 2009; Smith, 2013), and with neuroinflammatory conditions such as Alzheimer's disease and aging (Eikelenboom et al., 2002; Gimeno et al., 2009; Kuo et al., 2005; Piazza and Lynch, 2009 ). Neuroinflammation is characterized by increases in glia in the brain, particularly astrocytes and activated microglia that release inflammatory cytokines such as interleukins and chemokines. "
    [Show abstract] [Hide abstract] ABSTRACT: Tetramethylenedisulfotetramine (TETS) is a potent convulsant poison that is thought to trigger seizures by inhibiting the function of the type A gamma-aminobutyric acid receptor (GABAAR). Acute intoxication with TETS can cause vomiting, convulsions, status epilepticus (SE) and even death. Clinical case reports indicate that individuals who survive poisoning may exhibit long-term neuropsychological issues and cognitive deficits. Therefore, the objective of this research was to determine whether a recently described mouse model of acute TETS intoxication exhibits persistent behavioral deficits. Young adult male NIH Swiss mice received a seizure-inducing dose of TETS (0.15mg/kg, ip) and then were rescued from lethality by administration of diazepam (5mg/kg, ip) approximately 20min post-TETS-exposure. TETS-intoxicated mice typically exhibited 2 clonic seizures prior to administration of diazepam with no subsequent seizures post-diazepam injection as assessed using behavioral criteria. Seizures lasted an average of 72s. Locomotor activity, anxiety-like and depression-relevant behaviors and cognition were assessed at 1week, 1month and 2months post-TETS exposure using open field, elevated-plus maze, light↔dark transitions, tail suspension, forced swim and novel object recognition tasks. Interestingly, preliminary validation tests indicated that NIH Swiss mice do not respond to the shock in fear conditioning tasks. Subsequent evaluation of hot plate and tail flick nociception tasks revealed that this strain exhibits significantly decreased pain sensitivity relative to age- and sex-matched C57BL/6J mice, which displayed normal contextual fear conditioning. NIH Swiss mice acutely intoxicated with TETS exhibited no significant anxiety-related, depression-relevant, learning or memory deficits relative to vehicle controls at any of the time points assessed with the exception of significantly increased locomotor activity at 2months post-TETS intoxication. The general absence of long-term behavioral deficits in TETS-intoxicated mice on these six assays suggests that the neurobehavioral consequences of TETS exposure described in human survivors of acute TETS intoxication are likely due to sustained seizure activity, rather than a direct effect of the chemical itself. Future research efforts are directed toward developing an animal model that better recapitulates the SE and seizure duration reported in humans acutely intoxicated with TETS. Copyright © 2014 Elsevier Inc. All rights reserved.
    Full-text · Article · Nov 2014
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