DOI: 10.1002/JLB.3MR0118-003R
REVIEW
Innate immunity and cellular senescence: The good and the bad in the developmental and aged brain Antonietta Santoro1
Chiara Carmela Spinelli2
Stefania Lucia Nori1
Mario Capunzo1
Stefania Martucciello3
Annibale Alessandro Puca1,2 ∗
Elena Ciaglia1 ∗ 1 Department of Medicine, Surgery and Dentistry
“Scuola Medica Salernitana,” University of Salerno, Via Salvatore Allende, Baronissi, Italy 2 Cardiovascular Research Unit, IRCCS Multi-
Medica, Milan, Italy
Abstract Ongoing studies evidence cellular senescence in undifferentiated and specialized cells from tissues of all ages. Although it is believed that senescence plays a wider role in several stress responses in the mature age, its participation in certain physiological and pathological processes
3 Department of Chemistry and Biology, Univer-
sity of Salerno, Fisciano, Italy
throughout life is coming to light. The “senescence machinery” has been observed in all brain cell populations, including components of innate immunity (e.g., microglia and astrocytes). As the ben-
Correspondence Elena Ciaglia, Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via Salvatore Allende, 84081 Baronissi, Salerno, Italy. Email:
[email protected] ∗ Annibale Alessandro Puca and Elena Ciaglia are
eficial versus detrimental implications of senescence is an open question, we aimed to analyze the contribution of immune responses in regulatory mechanisms governing its distinct functions in healthy (development, organogenesis, danger patrolling events) and diseased brain (glioma, neuroinflammation, neurodeneration), and the putative connection between cellular and molecular events governing the 2 states. Particularly this review offers new insights into the complex roles of senescence both as a chronological event as age advances, and as a molecular mechanism of brain
considered co-last authors.
homeostasis through the important contribution of innate immune responses and their crosstalk with neighboring cells in brain parenchyma. We also highlight the impact of the recently described glymphatic system and brain lymphatic vasculature in the interplay between peripheral and central immune surveillance and its potential implication during aging. This will open new ways to understand brain development, its deterioration during aging, and the occurrence of several oncological and neurodegenerative diseases. KEYWORDS
brain aging, cellular senescence, development, immune cells, inflammation, neurodegeneration
1
INTRODUCTION
cause or the consequence of a given pathology, senescent cells have been found in a large number of diseases1 where they share features of
From its discovery, cellular senescence has always been linked with
irreversible cell cycle arrest and phenotypic alterations, including chro-
aging and age-related disorders. Without addressing if they were the
matin and secretome modifications. When cells become senescent, they undergo profound changes,
Abbreviations: AD, Alzheimer's disease; AMD, age-related macular degeneration; APP, amyloid precursor protein; ARF, ADP-ribosylation factor; BBB, blood-brain barrier; CDK, cyclin-dependent kinase; CDKN2A, cyclin-dependent kinase inhibitor 2A; CSF, cerebrospinal fluid; CSF1, colony-stimulating factor 1; DDR, DNA damage response; DG, dentate gyrus; GSC, glioma stem cell; HCC, hepatocellular carcinoma; IKK𝛽, I𝜅B kinase-𝛽; MM, multiple myeloma; MMP, matrix metalloproteinase; NEP, neuroepithelial progenitor cells; NPC, neuronal progenitor cell; NSC, neural stem cell; OPC, oligodendrocyte precursor cell; PD, Parkinson's disease; PTEN, phosphatase and tensin homolog; RAGE, receptor for advanced glycoxidation end-products; ROS, reactive oxygen species; SA-𝛽-Gal, senescence-associated-𝛽-galactosidase; SASP, senescence-associated secretory phenotype; STING, stimulator of interferon genes; SVZ, subventricular zone; VEGF, vascular endothelial growth factor
Received: 3 January 2018
Revised: 12 January 2018
J Leukoc Biol. 2018;103:509–524.
including the acquisition of a senescence-associated secretory phenotype (SASP), one of the elements distinguishing senescent from quiescent cells.2 Senescent cells secrete proteins, including cytokines and chemokines with proinflammatory properties (CCL2/MCP-1, TNF-𝛼, IFN-𝛾, IL-6, IL-8), growth factors (TGF-𝛽, HGF), and proteases (MMP1/3/10/13, where MMP is matrix metalloproteinase) that have autocrine and paracrine activities, mainly allowing crosstalk between senescent cells and neighboring cells. This local and systemic alteration of tissue milieus leads to the detection, elimination, and rapid
Accepted: 12 January 2018 www.jleukbio.org
c 2018 Society for Leukocyte Biology
509
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SANTORO ET AL .
replacement of senescent cells by the homeostatic protective system
of age-related pathologies,1 little is known about the induction of
of each tissue, but also to tumor formation and some age-related dis-
cellular senescence and the SASP in the brain. Here, environmental
orders when not properly regulated.1
and inner stressors may act in part by eliciting senescence and the
Senescent cells are detectable in the mammalian brain, specifically
SASP machinery within nonneuronal glial cells, thus contributing
in replication competent glial cells, where they could contribute to neu-
to the characteristic decline in neuronal integrity that occurs dur-
rodegeneration by secreting pro-inflammatory SASP factors and/or
ing brain aging. In this review, starting from a brief description of
deregulating cellular crosstalk useful for the structural and functional
the emerging role of senescence in different biological processes
neuron-glial interaction that maintains neuronal homeostasis.3 Senes-
(development, wound repair, oncogenesis, etc.) and of the reciprocal
cence markers have been observed in all the different cell popula-
influence with innate immunity in peripheral tissues, we will discuss
tions of the brain, including neurons and components of innate immu-
new emerging evidence indicating the existence of such a mechanism
nity, and they correlate with normal or pathological aging conditions.4
in developmental processes and in age-associated pathologies of the
Indeed, immune responses in the CNS are common, despite its per-
brain, in which microglia is recognized to be an essential player in
ception as a site of immune privilege.5 These responses are mediated
maintaining homeostasis.
by resident microglia and astrocytes, which are innate immune cells engaged in significant crosstalk with CNS-infiltrating T cells and other components of the peripheral innate immune system. Microglia and astrocytes, by interacting simultaneously with the peripheral immune system and typical brain cells, can lead to the resolution of infection, neurodegeneration, or neural repair and tissue development depend-
2 PERIPHERAL FEATURES OF SENESCENCE AND ITS ROLE IN NORMAL AND PATHOLOGICAL CONDITIONS
ing on the context.5 Very recently, Ablasser and colleagues6 illustrated how the entire
The concept of “cellular senescence” (or just “senescence”) was
process of senescence and the fast-acting, but unspecialized cells
originally formulated to describe the irreversible growth arrest of
of the innate immune system (macrophages, neutrophils, NK cells,
human fibroblasts after a finite number of divisions in culture.11
mast cells, etc.), share an overlapping mechanism of recognition of
Later, it was discovered that “replicative senescence” is linked to
aberrant self-molecule and microbial products, respectively. Follow-
telomere shortening resulting from consecutive cycles of DNA
ing defects in the integrity of the nuclear envelope, senescent cells
replication and cell division.12 Subsequent studies identified a
sense their own DNA, which activates the cyclic GMP-AMP synthase
“stress-induced senescence” independent from telomere erosion,
(cGAS)/stimulator of IFN genes (STING) pathway, a member of the
which was activated in response to a wide variety of stimuli, such
pattern recognition receptors, to regulate and facilitate the secretion
as DNA damage, oxidative stress, and activation of oncogenes.13–15
of inflammatory mediators of the SASP in an autocrine as well as a
Oncogene-induced senescence is due to activation of oncogenes,
paracrine manner by immune cells in vivo. These help the clearance
such as K-RAS, B-RAF, phosphatase and tensin homolog (PTEN), and
of aberrant senescent cells in various contexts of senescence, such
NF1, and is characterized by the derepression of the cyclin-dependent
oxidative stress, oncogene signaling, and irradiation, rather than fight-
kinase inhibitor 2A (CDKN2A) locus. Activation of the CDKN2A locus
ing off the pathogens.6 The study shows that DNA sensing through
produces the tumor suppressor p16 and ADP-ribosylation factor
the cGAS-STING pathway is an important regulator of senescence,
(ARF), causing growth arrest. This locus is repressed in young tissue
and the release of inflammatory mediators could serve as a surveil-
by polycomb group-mediated H3K27 methylation and H2A-K119
lance system that protects the organism against neoplastic cells and
ubiquitination, but becomes derepressed with aging or after tissue
in those conditions in which a programmed macrophage-mediated
damage.16 Oncogene activation has been reported to modulate
clearance of senescent cells is established, such as in organogenesis7
different pathways, many of which activate p53 and converge in
or tissue repair and fibrosis resolution.8 However, on the other face
the activation of the cyclin-dependent kinase (CDK) inhibitors p16,
of the coin, ones evoked and not self-resolving, the inflammatory
p15, p21, and p27, resulting in growth arrest.1 Telomere attrition
response can also contribute to the loss of tissue structure and func-
is sensed by cells as DNA damage, and like external DNA-damaging
tion by creating a chronic pro-inflammatory milieu leading to neurode-
agents, triggers the activation of the DNA damage response (DDR).
generation and cancer.9 Therefore, understanding the inner crosstalk
The DDR actives the ataxia-telangiectasia mutated and ataxia telang-
between innate immunity and cellular senescence might serve to iden-
iectasia and Rad3-related pathways, which in turn active the kinases
tify new drug targets to tackle diseases characterized by altered recip-
CDK2 and CDK1, respectively, determining p53-dependent cell
rocal interplay between different cell populations in organs, especially
cycle arrest.17 Reactive oxygen species (ROS) produced by exoge-
the CNS.
nous (such as radiation and smoke) and endogenous (mitochondria,
The occurrence of age-related neuropathology is increasing
RAS-RAF-MEK-ERK pathway) sources also induce senescence via
exponentially and has become a major public health concern in
mitochondrial and nonmitochondrial pathways, converging on p53,
recent years.10 Neuronal damage is believed to involve the induc-
pRB, p16, and p21,18 considered the main molecular players regulating
tion of neuroinflammatory events as a consequence of glial cell
cell senescence.
activation. Although cell senescence and the related inflammatory
Senescent cells are detected during embryo tissue development in
state in peripheral tissues has been causally linked to a number
highly differentiated and less-specialized cell types as well as during
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SANTORO ET AL .
tissue repair and tumor suppression responses.19 Aging accelerates
by also inducing T-cell senescence, probably in a paracrine manner
the rate of senescent cell accumulation, as evidenced by a progressive
by a bystander effect. As regarding the innate immune compartment,
increase in some senescence markers. The senescence phenotype is
following inflammatory stimuli the onset of cellular senescence also
indeed characterized by a collection of markers, which can be used for
influences the polarization of macrophages, which play a critical role
its identification in vivo and in vitro. Not all these markers are exclu-
in innate immunity, acting as sentinels to fight pathogens, promoting
sively specific for senescent cells, which in turn do not simultaneously
wound healing, and orchestrating the development of the specific
express all of the senescence markers. To summarize, cultured senes-
acquired immune response. Specifically, deficiency of p16INK4a and
cent cells change their morphology, becoming much larger, flat, and
p14/p19ARF senescence markers was responsible for the polar-
vacuolized. Further, they are nonproliferating cells and do not show
ization both of murine bone marrow-derived macrophages27 and
BrdU incorporation or Ki67 expression. The most used method is his-
adipose tissue macrophages28 toward an alternatively activated anti-
tochemical detection of senescence-associated-𝛽-galactosidase (SA-𝛽-
inflammatory state, as suggested by the up-regulation of genes asso-
Gal), which reflects increased lysosomal content. Other conventional
ciated with the M2 phenotype, such as ARG1 (arginase-1), and Ym1/2
markers are p16, ARF, p53, p21, p15, p27, and hypophosphorylated
compared with wild-type cells. Accordingly, in the in vivo setting, aging
retinoblastoma (RB). 𝛾-H2AX (a phosphorylated form of the histone
affects many aspects of the cellular function of macrophages by mainly
variant H2AX) is a most sensitive marker of dsDNA breaks and telom-
impairing phagocytosis, removal of debris at the site of injury, wound
ere shortening, and the number of 𝛾-H2AX-positive foci increases in
repair, and tissue regeneration in both humans and rodents. Aging may
damaged and senescent cells.20 DDR is associated with the appear-
impair phagocytosis of myelin debris by macrophages, a key prerequi-
ance of senescence-associated heterochromatin foci , which contain
site step for efficient myelin regeneration (remyelination), and accord-
di- or tri-methylated lysine 9 of histone H3 (H3K9Me2/3), a histone
ingly Ruckh et al. elegantly demonstrated that monocytes from young
proteins.21
mice have the potential to boost remyelination in old mice.29 In con-
H2A variant (macroH2A), and heterochromatin protein 1
p38MAPK
and
trast, in a mouse model of age-related macular degeneration (AMD),
NF-𝜅B) are responsible for the expression of a number of senescence-
macrophages from old mice were unable to inhibit angiogenesis fol-
associated transcripts, while hyporeplicative senescent cells are
lowing laser injury to the retina when in the presence of IL-10.30 The
metabolically active.22
loss of antiangiogenic function of senescent macrophages was likely
Activation of damage-sensing signaling pathways (e.g.,
Cells with features of senescence have been identified during mam-
caused by down-regulation of FasL, suggesting that old macrophages
malian embryonic development at multiple locations as a phenomenon
might actually promote abnormal angiogenesis, as seen in diseases of
that contributes to remodeling and organogenesis. In this case, cells
aging such as AMD, the leading cause of blindness in people over 50
are recognized and eliminated by macrophages to efficiently remodel
years of age, and certain cancers. Finally, known for their cytotoxic
and sculpt tissues and organs.23 A classic example of senescence-
and immunoregulatory properties,31 NK cells are prone to undergo a
ducts.23
Fur-
senescence program. To date, this has been described only in a well-
ther recent studies have demonstrated the influence of senescence
established physiological setting. Specifically, in early pregnancy, the
driven sculpting is the regression of female Wolffian
repair.25
induction of NK senescence by DDR signaling generates the sustained
Senescent cells have been identified at different sites in the mouse
SASP secretory phenotype that can promote vascular remodeling
embryo, including the apical ectoderma ridge, the neuronal roof plate,
effects.23 Of note, these innate immune cells have been shown to elim-
the mesonephros, and the endolymphatic sac. These cells are nonpro-
inate cells carrying allogeneic mitochondrial DNA.32 Nevertheless, it
liferative, SA-𝛽-Gal-positive cells expressing p21, p15, and mediators
remains unclear whether immunosurveillance might efficiently antag-
of SASP, but they do not show DNA damage and do not depend on p53
onize the accumulation of mitochondrial DNA mutations normally
and p16 expression.7,23
associated with—and generally viewed as an etiological determinant
in embryonic
development,7,23
wound
healing,24
and tissue
of—aging.33
2.1
Cellular senescence and immune cell functions
Through the important contribution of immune cells, cellular senescence can control tissue repair and the maintenance of organ integrity.
Features of senescence, particularly the telomere-dependent ones,
The exponential accumulation of senescent cells with age can result
are widespread also throughout the immune system where intrinsic
from an increase in senescent cell production and/or decrease in
senescence-inducing actors could drive or tune the terminal differenti-
cell clearance, which usually occurs under physiological states. Effi-
ation program of several immune cell types, such as megakaryocytes, T
cient clearance of premalignant senescent hepatic cells through an
cells, macrophages, and NK cells. Senescence ensures proper terminal
immune response has been documented by Lowe and colleagues.34
differentiation of megakaryocytic cells, myeloid-derived immune cells
This depends on an intact CD4(+) T-cell-mediated adaptive immune
from which blood platelets originate, supporting normal and pathologi-
response, which, however, requires monocytes/macrophages to fully
cal wound healing and immune responses.26
Further, markers of senes-
execute the clearance of senescent hepatocytes. Impaired immune
cence, including CDKN2A, are also involved in the decision by mono-
surveillance of premalignant senescent hepatocytes results in the
cytes to differentiate toward inflammatory M1 macrophages, which in
development of murine hepatocellular carcinomas (HCCs), showing
turn will participate in T-lymphocyte polarization toward senescence-
that senescence surveillance is important for tumor suppression in
inducing Th1 cells. Notably CD4+CD25HiFoxP3+ Treg cells exercise
vivo. Indeed, in response to acute or chronic tissue injury, innate and
their immunosuppressive functions and limit inflammatory responses
adaptive immune cells greatly contribute to the maintenance of tissue
512
SANTORO ET AL .
homeostasis and help ensure the long lifespan of multicellular organisms. Injured cells within altered tissues/organs may become function-
3 SENESCENCE IN THE BRAIN AND ITS PHYSIOLOGICAL ROLE
ally deficient, leading to either cell death or the onset of cellular senescence. In the latter case, induction of senescence not only prevents the
3.1
Senescence onset in different brain cell types
potential proliferation and transformation of damaged/altered cells, but also favors tissue repair through the production of SASP factors1
The presence of senescence in the neural roof plate and in the neural
that function as chemoattractants mainly for NK cells (such as IL-
tube of mouse embryo reveals the importance that such a programmed
15 and CCL2) and macrophages (such as CSF1 and CCL2), innate
mechanism has in the development of the CNS.7 The mammalian neu-
immune cells endowed with a well-known cell clearance activity. These
ral tube is a monolayer of pseudostratified neuroepithelial progenitor
innate immune cells mediate an external quality-control mechanism
cells (NEPs), which move their nuclei up and down the apical–basal
for stressed cells, commonly known as immunosurveillance. Regard-
axis during the cell cycle (interkinetic nuclear migration). Initially, NEPs
less of the mechanism, senescent cells usually up-regulated the NK cell
undergo symmetric division to generate and expand the neural stem
activating receptor NK group 2 member D (NKG2D) and DNAM1 lig-
cell (NSCs) pool. After their early expansion—approximately at mouse
ands, which belong to a family of stress-inducible ligands, an impor-
embryonic day 11—NSCs begin to divide asymmetrically, forming a
tant component of the front line immune defense against infectious
daughter and a differentiating cell. In the later stage of this neurogenic
diseases and malignancies. Upon receptor activation, NK cells can then
phase, intermediate neuronal progenitor cells are formed, migrate to
specifically induce the death of senescent cells through their cytolytic
the subventricular zone (SVZ), and divide symmetrically to produce
machinery. Remarkably, a role for NK cells in the immune surveillance
neurons. Finally, gliogenesis begins at embryonic day 17, generating
of senescent cells has been pointed out in liver fibrosis,35 HCC,36 multi-
astrocytes and oligodendrocytes.46 Markers of senescence have been
ple myeloma (MM),37 and glioma cells stressed by dysregulation of the
identified in vivo in the neural tube up to this stage of the neurogenic
mevalonate pathway.38
phase.7 NSCs persist in the subgranular zone of the dentate gyrus
With a similar mechanism, during liver fibrosis, p53-expressing
(DG) of the hippocampus and in the SVZ of the lateral ventricles in the
senescent liver satellite cells skewed the polarization of resident Kupf-
mammalian adult brain.47 The NSCs ensure brain homeostasis, repair,
fer macrophages and freshly infiltrated macrophages toward the pro-
and neuroregeneration in the adult, but undergo proliferation and dif-
which displays senolytic activity. In
ferentiation decline with age. The decreased neurogenesis correlates
the same way, F4/80+ macrophages are key players in the clear-
and contributes to age-related disorders in the human and in mouse
ance of mouse uterine senescent cells in order to maintain postpar-
model,48,49 and it is thought to be due to the senescence of progenitor
tum uterine function.40 Cancer is another common disease of aging,
cells. Diverse stimuli can induce senescence in NSCs in vitro, includ-
and it is now clear that dysregulations in key mediators of senes-
ing DNA damage,50,51 oxidative stress,52 and activated oncogenes.53
cence (e.g., telomerase, p16INK4 , p53, RB) may influence human cancer
Several in vivo studies have supported this hypothesis, demonstrat-
risk. Paradoxically, if aging leads to decreased regenerative capacity in
ing age-dependent increase in telomere shortening, p16INK4a expres-
the brain, conversely it increases the risk of tumorigenesis.41 While
sion, and ROS accumulation in mouse NSCs.54–56 NSCs are therefore
considered to be an antitumor mechanism for cancer prevention,42
the physiological reservoir for neurons, astrocytes, and oligondendro-
senescent cells, through the release of different cytokines, includ-
cytes, whereas microglial cells are the only cells in the brain deriving
ing IL-1 and IL-6, may also influence other cells in an autocrine
from hematopoietic precursors of the yolk sac; once migrated, they are
and paracrine fashion, both enhancing and dampening antitumor
self-renewed and do not require maintenance upon the recruitment of
responses. Indeed, the ability of the SASP to induce an immuno-
bone marrow-derived cells.57
inflammatory M1
phenotype,39
suppressive immune cell environment has recently been shown in a
Neurons are terminally differentiated, postmitotic cells that
mouse model of PTEN loss-induced cellular senescence in prostates
remain functional for the lifetime of the organism. Although these
with prostatic intraepithelial neoplasia.43 Senescence-recruited imma-
cells do not undergo replicative senescence, recent studies revealed
ture myeloid cells and macrophages cleared precancerous senescent
that neurons can show a stress-induced senescence-like phenotype.
cells, but later they were responsible for senescence-induced tumor
Increased 𝛽-galactosidase activity and mitochondrial dysfunction
activity.44
were observed in hippocampal neurons in long-term cultures in
Further, MM causes clonal T-cell immunosenescence and, accordingly,
vitro,58 and 𝛽-galactosidase-positive staining was detected also in vivo
the cells exhibited a senescent secretory effector phenotype: KLRG-
in the hippocampus of aging rat.59 Furthermore, in response to DNA
1+/CD57+/CD160+/CD28–. Tumor-induced senescent TCD8+ cells
damage, purkinje, hippocampal, and cortical mouse neurons exhibit
with suppressor function have been defined a potential form of tumor
different markers of senescence, including heterochromatinization,
immune evasion.45 This is in contrast with the above-discussed find-
synthesis of proinflammatory interleukins, and high b-galactosidase
ing of efficient immune cell clearance of senescent cells as an extrin-
activity. This p21-dependent phenotype is aggravated in the aged
sic antitumor barrier, suggesting a possible dual role of cellular senes-
mouse and attenuated by caloric restriction.60 Thus, senescent neu-
cence in tumor prevention and tumor progression. Future studies are
rons might contribute to brain aging as an important source of chronic
thus needed to fully understand which molecular and cellular factors
pro-inflammatory and pro-oxidant signaling.
growth promotion in mice, leading to inhibition of NK cell
secreted or overexpressed by senescent cells may determine the final outcome of immune responses.
Neuroglial cells, including astrocytes, oligodendrocytes, and microglia, represent a large component of the mammalian brain.
513
SANTORO ET AL .
Astrocytes and oligodendrocytes have an important supporting role in
The most important and beneficial cell types for maintaining normal
neural functions. In particular, oligodendrocytes produce the myelin
brain function are microglial cells, large macrophages that account for
that surrounds the axon of nerve cells and facilitates the conduction
∼15% of the brain's cellularity. Microglia preserve brain homeostasis
of signals. Changes in oligodendrocyte morphology, including the
by rapidly responding for clearance of invading pathogens, tissue
swelling of cell processes and the presence of inclusion bodies, were
debris, synaptic stripping, and remodeling.9 However, as we age,
observed in human aged brain, and were correlated with the progres-
microglia undergo a process of immunosenescence, characterized by
sive demyelination of nerves during aging and neurodegenerative
changes in morphology and a more reactive/activated phenotype.79
diseases. Magnetic resonance imaging has confirmed the reduction of
In aged brain, microglia from human cerebral cortex exhibit deram-
white matter volume and structural integrity both during aging and
ification, spheroid formation, and fragmentation of processes.80
in neurodegenerative diseases.61 The progressive loss in remyelina-
Telomere shortening has been seen to occur in rat microglia, both in
tion efficiency occurs because of an impairment of oligodendrocyte
culture after repeated cell division and in an advancing state in vivo.81
precursor cell (OPC) recruitment and the subsequent differentia-
Morphological abnormalities associated with the switch from an
tion into remyelinating oligodendrocytes.62 Furthermore, rodent
amoeboid to a ramified morphology were also observed in microglial
OPCs escape from replicative senescence in vitro,63 but acquire an
cells isolated from neonatal mice and cultured from day 2 to 16 in
ECRG4-mediated senescence phenotype when grown with serum.64
vitro.82 Biochemical alterations were also found, such as a reduction
Astrocytes, the most present glial cells, constituting about 50%
of MMP-9 and glutamate release, an increase in NF𝜅B activation,
of CNS cells,65,66 are active players in brain homeostasis and central
and a decreased expression of TLR-2 and TLR-4, resembling the
innate immunity. They react to different insults and injuries through
activated as well as senescent phenotype.82 Other authors reported
a spectrum of molecular, cellular, and functional changes, defined as
morphological changes in terms of size, heterogeneous cytoplasmic
astrogliosis.67,68 Senescence hallmarks have been detected in cultured
content, IL-1 expression, and transcription in the mesial temporal
astrocytes in response to oxidative stress. They involve morphologi-
lobe of normal aged individuals,83 suggesting that altered cytokine
cal changes, expression of p16, p21, p53, and p53-binding protein 1
and TLR expression profiles are associated—but not necessarily in a
(53BP1), cell cycle arrest, reduction in telomere length, and secretion
cause-effect manner—with the morphological changes in microglia.
In vivo, it is conceivable
Sierra et al.84 demonstrated that in aging mouse microglia in vivo,
that their age-associated changes are more complex than previously
there was a characteristic presence of lipofuscin granules, decreased
described and involve either the expression of the same senescence
processes complexity, altered cytoplasmic granularity, and increased
markers of other kind of cells or the production of specific factors
mRNA expression of either pro-inflammatory (TNF-𝛼, IL-1𝛽, IL-6)
required for the crosstalk with the neighboring cells. Aged hypothala-
or anti-inflammatory (IL-10, TGF-𝛽1) cytokines.84 Furthermore,
mic astrocytes from brain-specific I𝜅B kinase-𝛽 (IKK𝛽) knockout mice
in healthy adult and aged mice, RNA sequencing followed by RT-
show alterations in intracellular signaling pathways involved in neu-
PCR and fluorescence dual in situ hybridization has revealed that
roinflammation, such as activation of NF𝜅B and its regulatory proteins
microglia have a distinct cluster of transcripts encoding proteins for
IKK𝛽,70
also influencing microglia-neuron crosstalk. Mechanistic stud-
sensing endogenous ligands and pathogens, named the sensome.85
ies in this genetic model further showed that IKK𝛽 and NF𝜅B activation
With aging, sensome transcripts appeared down-regulated, whereas
inhibited gonadotropin-releasing hormone, promoting aging.70 More-
transcripts involved in microbe recognition and host defense were
over, it has been proposed that the functional decline of aged brain may
up-regulated together with an increase in the expression of genes
be due, at least in part, to decreased trophic support, changes in synap-
that promote neuroprotection.85 These parallel increases in both
of pro-inflammatory cytokines (SASP
like).69
astrocytes.71,72
In
pro-inflammatory and anti-inflammatory factors suggests that, even
agreement with this hypothesis, more recent in vitro studies demon-
though in aged microglia basal levels of these proteins are higher than
strated that hypothalamic astrocytes from aged Wistar rats are able
young microglia, cells are still able to self-regulate switching from the
to remodel and change their neurochemical properties compared to
classical M1 state to M2, promoting resolution of inflammation and
newborn and adult rats.73
Age-related variations were observed in the
restoring homeostasis.86 From this point of view, it has been proposed
regulation of glutamatergic homeostasis (with a significant reduction
that with age, microglia could be in a chronic state of neuroinflam-
of glutamate production in aged astrocytes), glutathione biosynthe-
mation. This implies that cells are already “primed” and, as in the case
sis, amino acid profile, and glucose metabolism. Additionally, increased
of peripheral macrophages, a secondary triggering stimulus induces
expression and activation of NF𝜅B and PI3K/Akt was observed, cor-
a more rapidly and greeter response in terms of pro-inflammatory
roborating that during aging physiological changes of astrocytes could
cytokines. Accordingly, some in vivo studies demonstrated that sys-
modify their impact on microglia and neuron functions. Moreover,
temic treatment with LPS to aged mice elevates the level of cytokine
studies on rat and human postmortem brain samples suggest a direct
production compared to young animals.87,88 Frank et al.89 examined
communication of astrocytes with microglia in aged brain, since it
age-related mRNA alterations of cell surface MHC class II in the
has been found that during aging, astrocytes from hippocampal sub-
hippocampus of older (24-month old) and younger (3-month old) male
regions (CA1, CA2, and CA3 sectors) have increased expression of
F344xBN F1 rats. They found that older animals exhibited increased
glial fibrillary acidic protein and vimentin74–76 and show a hyper-
mRNA levels of MHC class II, CD86, CIITA, and IFN-𝛾, while exhibiting
tic efficacy, and an increase in ROS production in
trophic
morphology77
microglial functions.78
typical of an activated state that can modulate
a reduction of molecules down-regulating macrophage activation, such as IL-10 and CD200. These findings corroborate the hypothesis
514
SANTORO ET AL .
that normal brain aging is characterized by a shift toward a chronic, but
leptomeninges, and periventricular regions [reviewed in Ref. 107]. In
physiological, low-grade pro-inflammatory state, which we can define
the light of these results, in our opinion we should revisit our traditional
as “brain inflammaging”. Indeed, inflammaging is referred to as a sub-
concept of the brain as an immune-privileged place: rather, it is a terri-
clinical chronic inflammatory process90,91 characterized by peripheral
tory with a double and cooperative immunity. From the inside, resident
immune innate activation and significant changes in monocyte and
microglial cells and astrocytes would control inflammation and coordi-
macrophage functions as well as by a parallel decrease in peripheral
nate brain response to peripheral attacks through its crosstalk with T
naive T cells and an increase in late-stage differentiated memory T cells
cells. From the outside, naïve myeloid precursors would be necessary
with a reduced antigen receptor diversity.92,93 However, changes in the
in the context of brain inflammation, injury or infection in which, as in
basal pro-inflammatory state of innate immunity both in the periphery
other body tissues, the general immune system must be recruited.104
and CNS have some similarities, and peripheral immunosenescense
The existence of this spatial, temporal, and functional cooperation
may contribute to neuroinflammation by modulating glial cells toward
has been reinforced by the recent discovery and description of both
a more active pro-inflammatory state.94 As an environmental sensor,
the brain glial-dependent lymphatic system, named the “glymphatic
microglia interact with the surrounding cells, astrocytes, oligoden-
system”108,109 and meningeal lymphatic vessels.110 The former is
drocytes, and neurons, so changes in microglia during brain aging are
composed from a wide network of paravascular pathways and astro-
expected to influence the functions of the other CNS cells.
cytes that connect cerebrospinal fluid (CSF) and its circulation with
Emerging evidence highlights that inflammaging modifies neuron–
interstitial fluids and the brain parenchyma.108–110 Although the glym-
astrocyte–microglia crosstalk and that this interaction could be
phatic system has been considered the essential fluid drainage system
responsible for brain aging and, when impaired, for neurodegenera-
responsible for transferring interstitial fluids and solutes including
tive disease.95,96 Microglia as a key immune regulator of CNS involves
misfolded proteins such as A𝛽 from the brain parenchyma to the
also the interplay with neurons. In aged brain, it appears that some lig-
CSF,108,111 how CSF can leave the CNS and entry into the deep cervi-
ands of the neurons for microglia-specific receptors, such as CX3CR1
cal lymph nodes has been a subject of interest for decades. This has led
and CD200 protein expression, decreased with increasing age, con-
to the discovery of a lymphatic vessel network lining the dural sinuses
tributing to establishing a pro-inflammatory phenotype.96–98 Finally,
in the mouse brain meninges.112 These structures express all of the
microglial activation results in the release of soluble factors that
molecular hallmarks of lymphatic endothelial cells, are able to trans-
can prevent TNF-𝛼-induced apoptosis of mature oligodendrocytes in
port fluid and immune cells from the CSF, and are connected to the
vitro.99 However, we have to take into account that most of the exper-
deep cervical lymph nodes, from which antigens may potentially induce
iments were carried out in animal models of neurodegeneration and
an immune response.110 Meningeal lymphatics are now considered
in experimental conditions of extreme activation of microglia, so the
a novel path for immune cells to egress the CNS under physiological
significance of such alterations in physiological conditions during aging
and pathological conditions, and its description challenges the dogma
remains to be elucidated.
that the immune privilege of CNS is in part due to the absence of CNS
On the other hand, microglia play also a role in neural progenitor
lymphatic drainage. Indeed, it is plausible that meningeal lymphatic
cell differentiation because they release soluble factors that exhibit
endothelial cells may have unique properties that induce and control
distinct effects on the different aspects of neurogenesis upon the acti-
CNS tolerance by shaping immune responses, as recently described
vation of TLRs100 ; this has led recently to the concept of “senescence
for lymphatic endothelial cells,113,114 using a transgenic mouse model
spreading” and/or paracrine senescence,101,102 which opens new ques-
expressing vascular endothelial growth factor (VEGF)-C/D trap and
tions into how dysregulated microglia can influence NSCs senescence
displaying complete aplasia of the dural lymphatic vessels. Aspelund
in the brain.
and co-workers112 demonstrated that the dura mater's lymphatic ves-
Even though glia (predominantly microglia and astrocytes) rep-
sels are very sensitive to the inhibition of VEGF-C/D signaling, since in
resent the main components of immunesurveillance in the CNS, and
these mice macromolecule clearance from the brain was attenuated,
cells of adaptive immunity cannot pass unrestrictedly the blood-brain
and transport from the subarachnoid space into deep cervical lymph
barrier (BBB), adaptive immune cells recruited from blood have been
nodes was abolished. Then malfunction of these meningeal lymphatic
found in several CNS-related autoimmune pathologies, such as multi-
vessels could be a cause of different pathological brain conditions in
ple sclerosis.103 Potential gates for leukocyte entrance are beginning
which altered immunity plays a key role, such as multiple sclerosis,
to be found [reviewed in Ref. 104], but how immune cells can reach the
Alzheimer's disease (AD), and possibly other aging-related disorders.
brain parenchyma, if they can recirculate, and the spatial and temporal
A significant decline in CSF outflow via meningeal lymphatics was
requirements that allow them to pass without compromising BBB
observed in aged mice, implying that meningeal lymphatic network
integrity are still matters of debate. It has been proposed that recir-
could be targeted for age-associated neurological conditions.115,116
culation of infiltrating immune cells from the brain parenchyma might not occur under physiological conditions,105 and the blood-meningeal barrier—which does not comprise astrocytes—could be more permis-
3.2
Developmental senescence in the brain
sive than BBB to immune cells entrance, allowing them to circulate
The role of senescence mechanisms in the acquisition of a properly
within the meninges.106 Moreover, MHC class II- and B7-positive
function of innate immune cells in CNS and in neuronal circuits they
perivascular macrophages, which are distinct from microglial resident
established is coming to the light. Cytokines and their receptors are
APC cells, have been described in the choroid plexus, dura mater,
expressed physiologically in CNS cells and are important for many
515
SANTORO ET AL .
neurodevelopmental processes and for the regulation of several spe-
during synaptic refinement.133 An additional function of microglia
cific area of the brain.117,118 A large number of pro-inflammatory
includes a significant contribution to synaptic stripping or remodeling
cytokines (e.g., IL-1𝛽, TNF-𝛼, TGF-𝛽) are expressed at high levels in
events.125 Activated microglia can up-regulate MHC class II surface
the developing CNS but at very low (constitutive) levels in the adult
expression and release cytokines, chemokines, nitric oxide, and sev-
brain. Coinciding with the appearance of amoeboid microglia during
eral neurotrophins, which regulate developmental cell death. Finally,
early brain development, researchers have reported a naturally occur-
microglia are observed within the myelin tracts during early develop-
ring increase in these cytokines suggesting their physiological role in
ment and changes in white matter microglia have been associated with
the development of specific brain area where they have been shown
deficits in oligodendroglia progenitor cells or myelination.134
to maintain neuronal identity and glial differentiation, proliferation,
Beside microglia, also astrocytes and oligodendrocytes have been
and synaptic maturation.119 For example, it has been demonstrated
characterized for their role in neuronal development. In mice, astro-
that active inhibition of bone morphogenetic proteins signaling, which
genesis starts around embryonic age 18 (E18) and lasts until approx-
are members of the TGF-𝛽 cytokine superfamily, is required for nor-
imately postnatal day 7. Astrocytes have precursors of neuroepithe-
mal neural development in mice.120 In rodents, IL-1𝛽 is produced at
lial origin, the above-mentioned neuronal progenitor cell (NPC),135
detectable levels within the cortex from approximately E14 to P7
that transform into radial glia. At the end of neurogenesis, radial glia
where it contributed to astrogliosis and neovascularization and has a
cells can differentiate into mature astrocytes characterized by changes
peak in the late development of cerebellum that occurs from P2 to
in morphology, connectivity, and electrophysiological properties.136
P14121
and also within the hippocampus; IL-1𝛽 levels are increased
Mature astrocytes were present throughout much of the normal CNS
nearly 6-fold at birth when compared to adult hippocampus.122 IL-6
at 15 weeks of gestation, but they vary in density in different parts.137
is important for numerous developmental processes including vascu-
Although astrocytes appear much later in the brain during develop-
logenesis of microvessel endothelial cells in murine prenatal brain.123
ment, it has been described that perinatal inhibition of astrogenesis
IL-6 increases markedly in striatum, hippocampus, and cortex through-
resulted in a drastic reduction in the density and branching of corti-
out development, suggesting a neurotrophic role for this cytokine
cal blood vessels suggesting to play a part in postnatal developmental
within these brain regions.124 All these data suggest that elevated lev-
angiogenesis.138 They were shown to be actively involved in the for-
els of particular cytokines may coincide with important processes of
mation and stabilization of blood vessel of the retinal vasculature139
neurodevelopment in a brain region-dependent manner. As this pro-
related to their properties to express the VEGF.140 Moreover, many
inflammatory secretory phenotype commonly belongs to senescent
studies suggest that astrocytes are involved in the formation and in the
cells characterized by a SASP phenotype, we might speculate that
maintenance of BBB properties141 by producing secreted molecules
senescence might also occur in and/or implicated in the fine tuning of
important for the regulation of interactions between BBB components
brain immune cells to maintain the brain integrity in early development
such as endothelial cells and pericytes.142,143
stage and in tissue repair processes.
Oligodendrocytes are highly specialized neural cells whose function
There are several reports indicating that microglial cells contribute
is to myelinate CNS axons. They are cells that form the fatty sheaths
to fetal brain development.125 In rat microglial cells are observed
that cover axons of neurons passing through the brain. It is becoming
in the developing brain at embryonic day 16 (E16) around subcorti-
more evident that glia-glia crosstalk plays several important roles in
cal regions.126 Microglial development occurs in parallel with neuro-
brain function during development [reviewed in Ref. 65]. In particular,
genesis in most brain structures.127 They arise from hematopoietic
astrocytes facilitate each step of myelination, including OPC prolifera-
stem cells in the yolk sac during early embryogenesis that populate
tion, differentiation, initial oligodendrocyte-axon contact, and myelina-
the CNS.128,129 The initial colonization of the brain by microglia cor-
tion. Moreover, other soluble factors secreted by astrocytes have been
responds to the vascularization of the CNS. During this time, cell-
implicated in enhancing myelination.65
cell communication continues between microglia and vascular sprouts, directly after they enter the neuroepithelium and throughout CNS development, suggesting a potential role for microglia in blood vessel formation.130,131 Therefore, in the human brain, microglia colonization coincides not only with vascularization but also with radial glia forma-
4 PATHOLOGICAL SIGNIFICANCE OF SENESCENCE IN THE BRAIN
tion, neuronal migration, and myelination.125 It has been speculated that microglia perform specialized functions
As innate immune cell functions decline with aging,144 process termed
critical to the development of the brain. For example, microglia appear
immunosenescence,90 it is tempting to speculate that a parallel decline
to influence events associated with neuronal proliferation and differ-
in cell clearance mechanism might occur as culprit in the deleteri-
entiation during development: microglia have the capacity to influ-
ous accumulation of senescent cells with aging. The immunological
ence the differentiation of adult and embryonic neural precursor cells
“silent” removal of apoptotic and increasing number of senescent cells
and it has been demonstrated that precursors depleted of microglia
might be compromised and may contribute to the pro-inflammatory
decreased precursor proliferation and astrogenesis, and these deficits
phenotype as discussed above. This might explain the most critical
could be rescued when microglia were added back to the cultures.132
change in the aging innate immune system, which is the increase in the
Additional function of microglia includes a significant contribution to
pro-inflammatory cytokines IL-1, IL-6, IL-18, and TNF-𝛼 suggestive of
synapse formation: they may remove complement-labeled synapses
a SASP phenotype145 and the consequent low-grade inflammation,
516
SANTORO ET AL .
contributing to immunosenescence and age-related disease, especially
recently demonstrated that glioma stem cells (GSCs) express and in
neurodegenerative disorders. Indeed when senescent cells were
turn induce the secretion by monocytic myeloid-derived suppressor
removed from aged mice artificially, the animals lived longer and were
cells, of many SASP factors, that can act as mediators of intercellu-
healthier.146 This was also confirmed by pharmacological approach
lar communication to promote systemic tumor immune escape. In par-
demonstrating that the “senolytic” clearance of senescent cells can
ticular, GSC-derived molecules are endowed with an immunomodula-
reduce age-related phenotypes.147 In the brain, the detection and the
tory activity that results in the suppression of peripheral T-cell immune
clearance of invading microorganisms and senescent cells as well as
responses. This is achieved by the engagement of cells of myeloid
surplus neurotransmitters, aged and glycated proteins, in order to
origins,156 which by losing their protective tumor surveillance function
maintain a healthy environment for neuronal and glial cells, is largely
clearly became cellular enemy in gliomagenesis.
confined to the innate immune system. Neuronal and glial cells express TLRs as well as complement receptors and virtually all complement components can be locally produced in the brain, often in response to
4.2
Senescence in brain neurodegenerative diseases
injury or developmental cues148 or to finely orchestrate wound repair
Neurodegeneration is characterized by synaptic loss and neuronal
as for microglial cells.149 In this context, it is tempting to speculate that
death resulting in mental impairments and functionality. It is commonly
immunosurveillance mechanisms may be in place to preserve neuronal
accepted that chronic inflammation contributes to neuronal degen-
homeostasis, and that the aging-related failure of such systems, for
eration. Neural damage in the CNS preferentially involves the acti-
the inner progressive decline in immune effector function, may allow
vation of the resident glial cells: microglia and astrocytes.157 How-
the development of neurodegenerative disorders and at least under
ever, activated innate immunity in the brain is able to elicit a strong
some circumstances, tumor occurrence. In the brain, innate immunity
adaptive immunity reaction through accumulation of misfolded pro-
responds differently to all kind of attacks, which can be divided
teins inducing neuroinflammation and long-term, low-grade sustained
essentially into 4 groups: acute injuries comprising traumas, ischemic
inflammatory factors that stimulate chronically both innate and adap-
stroke, and so on; neurodegenerative chronic disease (AD; Parkinson's
tive immunity.158 In this context, both AD and PD are age-related neu-
disease [PD], amyotrophic lateral sclerosis, and multiple sclerosis);
rodegenerative pathologies characterized by accumulation and aggre-
brain tumors (gliomas, glioblastomas, etc.); and infections (Escherichia
gation of misfolded proteins: the A𝛽 peptide in the first case and the
coli, HIV, etc.).9 Here, we would provide an overview on the knowl-
𝛼-synuclein in the latter.
edge of the relationship between innate immunity, senescence, and
AD is a neurodegenerative disorder characterized by progressive
brain pathologies, focusing on brain aging-related neurodegenerative
loss of neuronal functions leading to cognitive and functional impair-
disease and cancer.
ment and memory loss. The main pathological hallmarks of AD are the abnormal cerebral production and accumulation of A𝛽 peptide—
4.1
generated by the proteolytic cleavage of the amyloid precursor pro-
Senescence and brain cancer
tein (APP) in neurons—and the deposition of neurofibrillary tan-
Age is a strong predictive factor in the occurrence of glioma, the
gles (composed of hyperphosphorylated tau protein) within the brain
most aggressive adult brain cancer.38,150 Little is known about how
parenchyma and blood vessels.
aging increases glioma malignancy151 but recent studies highlighted
In AD, A𝛽 is present in the extracellular environment in various
the contribution of a pool of dysregulated NPCs with an increased
aggregation states (A𝛽 oligomers, fibrils, and plaques).159 As A𝛽
tendency to undergo senescence as opposed to proliferation and self-
oligomers accumulate, they prime microglial cells promoting their acti-
renewal in response to growth signals. Indeed, genome-wide associ-
vation and thus generating a pro-inflammatory status that perpetuates
ation studies and candidate analysis have identified noncoding reg-
and completely changes extracellular environment. It has been demon-
ulatory polymorphisms near the CDKN2A locus, producing p16INK4
strated that A𝛽 oligomers can interact with several receptors including
and ARF, that affect the lifetime risk of glioma.152 Telomere main-
TLR2, TLR4, CD14, CD36, and CD47 both in vivo and in vitro.160–163
tenance has emerged as another important molecular feature with
More recent results have demonstrated that ablation of TNF-RI/RII
impacts on adult glioma susceptibility and prognosis,152,153 suggest-
expression in a mouse model of AD can enhance pathology,164
ing that telomere biology and induction of replicative senescence may
suggesting that increased expression of TLR receptors and inflamma-
have a role in gliomagenesis. In glioma, the loss of immunesurveillance,
tory mediators can contribute to disease progression. Moreover, some
due to “immunosenescence”, may contribute to age-related increases
studies in vitro revealed that microglia are able to clear fibrillar A𝛽 acti-
in glioma incidence. One recent study showed that the decreased pro-
vating phagocytosis via CD14, TLR4, TLR2, and 𝛼6𝛽1 integrin.165,166
duction of CD8+ T cells is associated with increased glioma malignancy
Microglial cells also produce intracellular and extracellular proteases
in both aged human patients and a knockout mouse model.154 Further
such as neprilysin- and insulin-degrading enzyme eliminating A𝛽
gliomas activate microglia, but inhibit their phagocytotic activity and
soluble oligomers.167 These observations suggest that microglia acti-
enhance expression of pro-migratory
metalloproteases.155
Undoubt-
vation could participate to limit disease progression; however, when
edly, the major contributing factor to glioma development and progres-
A𝛽 production exceeds microglial ability to clear the toxic oligomers,
sion is its ability to evade the immune system. To date, only 1 evidence
microglia enter in an unresolving circuit of inflammation that has
would suggest the occurrence of an aberrant senescent program as a
been defined “frustrated inflammation.”9 Results obtained in animal
al.156
model and in vitro cultures of murine microglia are corroborated by
strategy of immune evasion in brain cancer. Indeed, Domenis et
517
SANTORO ET AL .
studies in humans. Human primary microglial cells are activated with
bradykinesia, rigidity, postural instability, and gait imbalance. The
the treatment of A𝛽 oligomers and exhibit up-regulated mRNA and
motor symptoms are generally considered the consequence of the
protein expression of pro-inflammatory cytokines including IL-1𝛽,
loss of dopaminergic neurons in the substantia nigra pars compacta of
IL-6, MCP-1, TNF-𝛼, and the chemokines CXCR2, CCR3, CCR5, and
the midbrain. The main pathological hallmark of PD is the deposition
TGF-𝛽.168 The overexpression of such a kind of cytokine milieu was
of an intracellular fibrillar and misfolded protein named 𝛼-synuclein
also found in human cortex of postmortem AD brains and in the CSF of
(Lewy bodies) causing a complex immunopathogenic response leading
Noteworthy, microglia, astrocytes, endothelial cells,
to PD.181 The etiology of the disease is still unknown; several studies
and neurons also express the receptor for advanced glycoxidation
in disease animal models suggest that PD could be a T-cell-dependent
end-products (RAGE), a cell surface receptor that is able to interact
autoimmunity associated with neuronal death. It has been demon-
with A𝛽 peptide and oligomers.169 Blocking the interaction of A𝛽 with
strated that CD4+ T cell expressing altered levels of the dopamine
RAGE impaired the activation of microglia and reduced the production
receptor D3 favors acquisition of the Th1 inflammatory phenotype,182
of proinflammatory mediators [reviewed in Ref. 170]. RAGE is also
whereas other authors proposed that T cells specific for the neurome-
suggested to play a key role in the clearance of A𝛽 and to be involved in
lanin can activate neuromelanin-specific B cells leading to the produc-
apoE-mediated cellular signaling, a family of proteins widely expressed
tion of autoantibody. In any case, stimulated T cells are able to infiltrate
in brain cells that by binding their receptor activate different cell kind
into the brain and activate resting microglia and astrocytes,181,183,184
dependent signaling pathways regulating the whole cellular crosstalk
finally causing neuroinflammation. On the other hand, microglia are
in the brain.171,172
able to recognize and phagocytize extracellular 𝛼-synuclein aggregates
AD
patients.9,169
As astrocytes display pleiotropic functions beyond their involve-
and are also activated by neuronal cell death itself. It has been shown
ment in supporting cells of the brain, data are accumulating on the role
that released extracellular 𝛼-synuclein or protein aggregates deriv-
of astrocytes in AD pathogenesis and progression. AD patients show
ing from neuronal death can be internalized by microglia through a
hypertrophic astrocytes associated with changes in GABA signaling
lipid rafts-mediated mechanism in BV2 cells.169,185 In a primary mes-
and recycling, potassium buffering, and in cholinergic, purinergic, and
encephalic neuron-glia culture model of PD, 𝛼-synuclein is phagocy-
calcium signaling.173 This phenotype, referred to as “reactive astro-
tosed by microglia resulting in increased pro-inflammatory cytokine
It
and chemokine production and activation of NADPH oxidase,186 which
has been shown that in mouse models of AD (5xFAD and APP/PS1
is the main source of ROS production in activated microglia. Accord-
mice), reactive astrocytes in the DG dramatically up-regulate intracel-
ingly, enhanced levels of IL-1𝛽 and IL-6 were found in plasma, nigros-
lular GABA levels compared with astrocytes from age-matched wild-
triatal regions, and CSF of PD patients compared to healthy aged
cytes”, presents a morphology resembling senescence
GABA levels were inversely correlated with the dis-
subjects.187,188 The high pro-inflammatory activation of microglia can
tance to amyloid depositions, suggesting that both hypertrophy and
be ultimately responsible for the recruitment of CD4+ and CD8+
GABA accumulation can be initiated by amyloid-related processes.174
T cells in the brain as found in PD animal models.189 Interestingly,
These results were corroborated by Brawek et al.176 who showed
Watson and colleagues190 followed the regional and temporal pattern
that in amyloid-depositing mice, astrocytes accumulate around senile
of microglial activation production in mice overexpressing wild-type
type
mice.174,175
phenotype.69
plaque, increased in soma size, and produce higher levels of GABA not
human 𝛼-synuclein. They showed that after 𝛼-synuclein overexpres-
only in DG but also in frontal cortex, suggesting that altered GABA
sion, microglia were activated in the striatum already at 1 month of
production could be a general astrocyte dysfunction in AD. Interest-
age and only after 5 months in the substantia nigra, but not in the cere-
ingly, it has been shown that brain tissue from aged individuals and
bral cortex or cerebellum. The pro-inflammatory cytokine production
p16INK4a
and MMP-1
was observed only after 5–6 months of age in the brain region where
both markers of the SASP phenotype together with increased produc-
microglia was found initially activated, indicating that 𝛼-synuclein
tion of pro-inflammatory cytokines, such as IL-6.177 Moreover, other
overexpression causes a selective early inflammatory response that
authors have demonstrated that A𝛽 can act as an NF𝜅B activator lead-
was exacerbated in aged subjects together with the overexpression
ing to the release of the C3 complement component in a mouse model
of TLR4, TLR6, and TLR2 (until 14 months of age) and the recruit-
of AD. The C3 component can bind C3a receptor on neurons, thus influ-
ment of CD4- and CD8-positive cells.190 It has been also shown that
encing dendritic morphology and cognitive functions.178
TLR2 binds directly to fibrillary 𝛼-synuclein triggering TNF and IL-
patients with AD exhibit higher expression of
Finally, the glymphatic-mediated clearance of A𝛽 peptide is highly
1𝛽 production,191 whereas TLR4 by interacting with 𝛼-synuclein can
relevant in AD since emerging results underlined that age-related
mediate its uptake promoting a pro-inflammatory status character-
cerebral lymphatic vasculature shows reduced drainage of intersti-
ized by cytokine production and ROS generation in both microglia and
tial fluid and solutes, possibly leading to failure of elimination of A𝛽
astroglia.192,193 Soluble fibrillar 𝛼-synuclein recognized by cell surface
oligomers and promoting A𝛽 deposition in the brain.179 Accordingly,
receptors such as TLR2 and TLR4 can trigger NF𝜅B-dependent pro-
recent results reported in a mouse model of AD that glymphatic trans-
inflammatory gene expression and up-regulates NLRP3 component of
port was reduced, and this led to the accumulation of toxic A𝛽 soluble
the inflammasome, a cytosolic signaling complex required to transform
oligomers,180 suggesting that restoring glymphatic functionality could
inactive IL-1𝛽 and IL-18 in their active forms, thus further promoting
be a therapeutic target to slow the onset of AD.
neuroinflammation.194 Interestingly, the inflammatory process seems
PD is the second most common neurodegenerative disease after
to be regulated by small microRNAs, as in a mouse model of PD pro-
AD resulting of aging. Clinically, it is characterized by resting tremor,
duced by adeno-associated virus-mediated expression of 𝛼-synuclein,
518
SANTORO ET AL .
the loss of miR-155 reduced pro-inflammatory responses including
between immune cells (especially innate immune cells) and senescence
cytokine release, nitric oxide synthase production, and MHCII expres-
might be the common denominator in its different faces (Figure 1).
sion, thus blocking
neurodegeneration.195
This is in agreement with
During brain development, a large number of immune molecules
other reported data suggesting that the inhibition of IFN-𝛾 and TNF-
belonging to SASP seem to be involved in several aspects of “building
𝛼 production by microglia and astrocytes could be used as therapeu-
brain,” such as neuronal and glial differentiation, synaptic maturation,
tic strategies to delay neuronal degeneration in PD.196,197 As in the
and vasculogenesis through the important contribution of microglia
case of AD, the production of the above-reported pro-inflammatory
and astrocytes. Indeed, senescence and the related SASP response
cytokines are indicative of a SASP phenotype of microglia and astro-
is not a singular state and its final outcome can be influenced by
cytes that could contribute to PD progression. In this context, it has
several factors. Many of them are the peculiar molecular and cellular
been reported that environmental stressors including pesticide expo-
sensors of the tissue microenvironment triggering senescence both
sure and ROS induction caused by glutathione depletion activated
in the presence of external stressors inducing DNA damage and ROS
SASP-associated inflammatory pathways (NF𝜅B and p38MAPK) and
production and in the context of development and aging with the aim
stimulated secretion of the SASP-associated cytokine IL-6 enhancing
to promote tissue remodeling and repair. In the pathological context, it
PD risk factors.167
would be necessary to understand if the senescence that is observed in
Many other cellular processes not fully explored could be impli-
brain cells during the various neuropathologies is part of their etiology
cated in promoting neurodegeneration, especially macroautophagy.
and supports their progression, or their appearance is a consequence
From this point of view, the emerging literature demonstrates that
of the same disease. From a molecular point of view, DNA and stress
the co-chaperone and anti-apoptotic BAG3 protein,198 expressed
molecules sensing mechanisms, which regulate SASP, might have a
in glial cells and neurons during brain development and neu-
putative role. Senescence induction might be triggered first as pro-
ronal
differentiation,199
could enhance the ability of astrocytes
tective response to inner and environmental stressors encountered
to clear misfolded and aggregate proteins released from neurons,
during the life, but if sustained over the time or not properly regulated,
contributing to maintain tissue homeostasis probably also partic-
it might favor the insurgence of disease and other adverse effects of
ipating to the cytoskeletal remodeling that astrocytes undergo
senescence in vivo. Microglia might represent an essential cellular
during astrogliosis.200
component with the capacity to oscillate among some physiological
Although it is clear that glia activation is a key event in neurodegen-
and pathological conditions. It regulates neuronal plasticity in the
eration, it is still debated if innate immunity activation precedes or is
brain during development and by buffering neurotransmitters and
the consequence of neuronal death in both PD and AD201 and what
ions, modulates local blood flow, thus contributing to the permeability
is the exact role of adaptive immunity in neurodegeneration during
of BBB. This, together with SASP-specific chemokines produced also
aging. However, from the overall findings, it appears that the immune
by other patrolling brain cells like astrocytes and following senes-
response to protein accumulation triggers deleterious events such as
cence of endothelial cells, could in turn recruit immune cells from the
oxidative stress and cytokine receptor-mediated cell death, which lead
periphery, functioning as the main orchestrator of cell communication
to neuronal loss. As the inflammatory tissue milieu is the fil rouge
in the brain. The fine tune and the reciprocal influence of different
of all these aging-related disorders, an imbalance in DNA and stress
kind of cells and mediators, required to initiate senescence and its
molecules sensing mechanisms, which regulate SASP,6 might also be
spreading to neighboring cells, explain why any alteration of this
responsible for. Indeed, it is now commonly accepted that the acti-
sickly equilibrium can lead to the appearance of those conditions in
vation of glia can be neuroprotective in the first stage of the disease
which senescence has known detrimental such as neuroinflammation,
but the chronic innate immune activation could lead to a closed cir-
neurodegeneration, and glioma onset. We have also to stress that even
cuit of autosustaining inflammation involving also T-cell infiltration
though the basal levels of pro-inflammatory cytokines and chemokines
from the periphery that can favor disease progression. Future studies
are higher than in young brain, the increase in pro-inflammatory
addressing if and how pathways of senescence induction and innate
mediators in aging brain, that we could define the “brain SASP pheno-
immune responses are intimately connected will allow the identifica-
type,” are not associated necessarily with pathologies; on the contrary,
tion of novel target of pharmacological interventions to ameliorate
they serve to resolve inflammation processes by self-regulating
age-related brain disease.
and eliminating pathogens and aggregation of detrimental proteins. In this context, we believe that the time passed since senescence initiation and its paracrine effects on tissue milieu is another clue influencing the balance in senescence response; when the immune
5 CONCLUSIONS AND FUTURE DIRECTIONS
response is exacerbated by the presence of excessive stimulation, protective inflammaging may shift toward a detrimental process of neuroinflammation favoring neurodegeneration and cancer. Indeed,
As we have summarized in this paper, compelling evidence exists that
senescence features of innate immunity, in terms of morphological
the role of senescence is no longer restricted to the context of stress
changes and chronic subinflammatory status, play major role in AD
and cellular damage. In peripheral tissues and partly in brain, it occurs
and PD, however further studies are needed to find the threshold
in regulating both physiological and pathological conditions. Even
of proinflammatory status over which the disease ensues and then
though its occurrence in CNS begins to be elucidated, the interplay
innate immunity promotes rather than limits the disease. Moreover,
519
SANTORO ET AL .
& NT E PM IS LO NES E V E DE OG E U AN SS RG I O T
TU
NI N RE G O SP F ON IMM SE UN S E
↑ Influx of PBMC via BBB distruption upon EC senescence
REP A RES IR AND OLU F TIO IBROS N IS
UE
↑ pro-migratory MMPs ↓ Brain Tissue Structure and other SASp factors by for Immunesenescence of gloma-activated microglia microglia and astrocytes ↑ putative clearance of senescent pre-cancerous cells by Microglia and NK
TISS
N SIO EVA M UNE IS IMM CHAN ME
↑ Inflammaging ↑ Neurogenesis due to Senescence of NPCs ↑ Neuroinflammation Neurotrophic Role & ↑ Aged M2 ↑ Vasculogenesis microglia by SASP ↑ Clearance of aberrant proteins ↑ T-cell suppression by senescent GSCs ↓ Myelination due to OD senescence
IMMUNESURVEILLANCE F I G U R E 1 The effects of cellular senescence in different biological processes mediated by the innate immune system in the brain are schematically summarized. Conditions in which senescence are known beneficial (indicated in green) or detrimental (indicated in red) are listed. SASP, senescence-associated secretory phenotype; NPCs, neuronal progenitor cells; OD, oligodendrocytes; BBB, blood-brain barrier; GSCs, glioma stem cells; MMPs, matrix metalloproteinases
more extensive studies have to be performed to better clarify the
data; A.A.P. and E.C. wrote the paper, critically discussed literature,
role of astrocytes dysfunction in AD pathogenesis and progression
and coordinated the research. All authors approved the final version to
and to establish whether astrocyte senescence in AD precedes or
be published.
follows A𝛽 deposition. Further given the importance of the glymphatic system and the meningeal lymphatic vessels as part of a bidirectional
ACKNOWLEDGMENTS
transporter system of solutes and immune cells outside the brain toward deep cervical lymph nodes and inside the brain through perivascular/meningeal pathways, major efforts are needed to verify the senescence occurrence as molecular driver during their generation and lifespan. On the other hand, the deleterious effect of aging and the hypo- or hyperfunction of this connection in neuroinflammatory
This study was supported by University of Salerno grant ORSA 177721 to A. Santoro. E. Ciaglia was supported by a fellowship from Fondazione Umberto Veronesi (FUV 2017, cod.1072 & FUV 2018, cod.2153) (Ministry of Health (ricerca corrente) and PRIN-20157ATSLF_009 to A.A.P.).
and neurodegenerative conditions (especially those associated with protein accumulation) should be also addressed by future researches. In conclusion, understanding the biological and molecular bases of
DISCLOSURES The authors declare no conflicts of interest.
senescence, and the interplay between cellular senescence and innate immunity, which controls distinct functions in healthy and disease brain, is a challenge and an opportunity that has a clinical importance and can lead to identify new pharmacological targets to maintain or restore, when dysregulated, the physiological functions in long-lived individuals.
AUTHORSHIP All authors checked literature data articles and reviews. A.S., C.S., S.M., S.L.N., and M.C. wrote the paper and critically discussed literature
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How to cite this article:
Santoro A, Spinelli CC, Martuc-
ciello S, et al. Innate immunity and cellular senescence: The good and the bad in the developmental and aged brain. J Leukoc Biol. 2018;103:509–524. https://doi.org/10.1002/JLB. 3MR0118-003R
