Immune system and central nervous system crosstalk: focus on IL-18 in neurodegenerative and psychiatric diseases
Author(s)
Palladino, Ilaria
Date Issued
May 31, 2013
Type
Doctoral Thesis
Abstract
In recent times, researchers are focusing more of their attention on the
crosstalk between the immune system (IS) and the central nervous system
(CNS). The possibility of active interplay between brain and immunity is
increasing, with evidence pointing out that circulating immune signals exert
an effect on the brain, and that brain-derived signals, in turn, may influence
immune reactions.
The interaction element between the molecules of the immune system and
CNS components is the blood brain barrier (BBB). In the past, BBB was
considered primarily a static barrier which prevented infiltration of immune
elements into the brain. Today, BBB is seen as an active regulatory interface
which controls the exchange between the brain and the periphery, and is
modified and affected by circulating events and by events on the CNS side
(McAllister AK, 2009).
The study of communication between IS and CNS is particularly crucial in
pathological situations. Our understanding of it may help to define the
etiology and the clinical progression of a number of diseases, including
CNS disturbances.
Research at present is aimed at defining the involvement of cytokines as
soluble factors which take part in the crosstalk between IS and CNS. In
particular, our attention has centered on interleukin (IL)-18, a proinflammatory
cytokine that is attracting growing interest for its role in the
brain, where it is constitutively present (Sugama S, 2006; Alboni et al,
2010). Furthermore, IL-18 can be up-regulated in aging (Dinarello et al.,
2006), as well as in several pathologic conditions, such as neuropathological
diseases and psychiatric illness. Of note, an abnormal expression of IL-18
has been observed both centrally and peripherally in progressive
neurodegenerative disorders, such as Alzheimer’s disease (Ojala et al.,
2009; Bossù et al., 2010) and in some psychiatric disorders affecting both
young and aged subjects (Reale et al., 2011). IL-18 is part of a system
composed by the same IL-18 and by receptor and soluble molecules.
Among the soluble molecules of the system, the most important is the IL-18
2
binding protein (IL-18BP), which is able to inhibit IL-18’s activity. In
addition to having neutralizing activity, IL-18BP can also induce a negative
feedback regulation of IL-18 production itself, by modulating the strong
increase of IL-18 in pathological circumstances (Novick, Schwartsburd,
Pinkus et al., 2001). Understanding how the IL-18 system is modulated
during neurodegenerative and psychiatric illnesses such as Alzheimer’s
disease and schizophrenia may be relevant to the comprehension of
inflammatory pathways leading to neurodegeneration and behavioural
disturbances.
Accordingly, the study I performed during my Ph.D was primarily aimed at
identifying IL-18 as a crucial participant in immune-brain crosstalk. The
study developed along three main lines: an animal model of chronic
neuroinflammation, and two clinical studies: one involving patients with
neurodegenerative loss of cognitive functions, the other with psychotic
disturbances.
Previous studies have shown that animals peripherally treated with a single
high dose of the bacterial endotoxin component lipopolysaccharide (LPS)
developed a persistent chronic brain inflammation characterized by
increased brain levels of TNF-α, accompanied by neuronal death and
impacting behavioural/cognitive performances (Qin et al., 2007; Semmler et
al., 2007). Thus, in the animal study of my PhD, a single intraperitoneal
administration of LPS (5mg/kg) was injected in male rats. After 7 days and
again after 10 months from the LPS administration, the rats were subjected
to behavioral/cognitive tests and scarified, to evaluate the amount of IL-18
and TNF-α in different brain areas such as frontal cortex, hippocampus,
hypothalamus, striatum and cerebellum. The single peripheral
administration of a high dose of LPS induced a persistent
cognitive/behavioral impairment, characterized by locomotor and
motivational/attentional deficits which appeared after 7 days and persisted
through 10 months of the treatment.
Regarding the brain production of cytokines, TNF-α was significantly
elevated in the frontal cortex and hippocampus of rats treated with LPS, in
comparison to rats of the control group, appearing after 7 days and
persisting after 10 months of the treatment. In addition, TNF-α levels were
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increased even in the cerebellum 10 months after LPS treatment. On the
contrary, IL-18 was persistently induced in frontal cortex, hippocampus and
cerebellum only after 10 months from the treatment, thus assuming that this
cytokine is involved lately in the inflammatory response.
These results suggest that IL-18 is a mediator of immuno-brain crosstalk,
and brain IL-18 production may be relevant to chronic neuroinflammation,
progressive cognitive impairment and behavioural disturbances.
The research has therefore shifted from a study on animals to a clinical
setting. To investigate the involvement of IL-18 in the progression of a
neurodegenerative disease, we have conducted our study on patients at high
risk to develop Alzheimer’s disease (AD). AD is characterized by
neurodegeneration, chronic neuroinflammation and progressive loss of
cognitive functions. Several studies have highlighted the possible role of
this cytokine in AD.
In particular, Ojala and colleagues. (Ojala et al., 2009) have done postmortem
studies on the brains of AD patients. The studies showed a
significant increase of IL-18 in the frontal cortex of patients compared to
controls. Moreover, many studies were conducted to determine the effect of
IL-18 on the progression of AD. The high levels of this cytokine have been
recently correlated with high levels of cognitive impairment (Bossù et al.,
2008).
It therefore seemed potentially interesting to study the role of IL-18 in
cognitive impairment and, particularly, in the pathogenesis of AD. Since
AD displays its first symptoms only after the pathology is already
established, or specifically when the neuronal loss is already in advanced
state, than it is impossible to study the inflammatory parameters in the early
stages of pathology on already diagnosed AD patients. To get around this
obstacle, the study has been focused on Mild Cognitive Impairment (MCI)
subjects who have: 1) a very early state of memory impairment, and 2) a
high potential for developing AD.
This study has been developed on two levels: one at serum level; and the
other one at cellular level. The IL-18 system has been evaluated in the
serum of MCI subjects vs. healthy controls (HC). Although there were no
significant differences between the serum levels of IL-18 system in the two
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groups, a significant correlation between serum levels of IL-18BP and
cognitive impairment of MCI subjects was identified.
Since then, we have continued the work on MCI subjects at a cellular level.
In particular, we have evaluated the levels of IL-18 and of other proinflammatory
cytokines (TNF-α and IL-1β) in the cell supernatants obtained
from PBMC in culture stimulated with LPS (200ng/ml). This study, which
was conducted on the MCI subpopulation of amnesic type (divided into
amnesic single domain MCI and amnesic multidomain MCI), in comparison
with the healthy controls, showed a selective augment of IL-18 in the
subpopulation of amnesic single domain MCI. This subgroup has the
highest chance of developing dementia typical of AD.
All of these results strongly indicate that IL-18 may be implicated in the
early pathological stages of AD, likely playing a role in the progression of
cognitive impairment.
The last part of my Ph.D study has been focused on investigating the
involvement of IL-18 system in the progression of psychotic disorders, in
particular schizophrenia (SCZ). It has been theorized that IL-18 may be
connected to this illness. In particular, five polymorphisms in genes related
to the IL-18 pathway, including IL-18 receptor genes, have been associated
with SCZ (Shirts et al., 2008). Furthermore, some variants of the IL-18
gene have been recently related to the development of SCZ symptoms (Liu
et al., 2011), and the levels of IL-18 circulating protein have been found to
be augmented in affected patients, as compared to those in controls (Tanaka
et al., 2000; Reale et al., 2011).
The modulation of IL-18 system in SCZ is unknown as yet, and therefore it
was interesting to evaluate the level of IL-18 system molecules in the serum
of SCZ patients. Indeed, IL-18 system seems to be deregulated in SCZ vs.
health controls. In fact, SCZ patients have exhibited a significant raise of
both IL-18 and IL-18BP. In particular, the increase of IL-18BP implies that
the natural inhibitor of IL-18 is trying to mitigate the pro-inflammatory
response of IL-18 likely triggered by the SCZ pathological pathways. As a
consequence, the final amount of the active form of IL-18 did not differ
between SCZ and HC. Moreover, the IL-18 system seems to be altered in
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particular in young SCZ, where an increase of the active circulating form of
IL-18 was selectively observed.
In conclusion, my Ph.D research has highlighted the possible involvement
of the pro-inflammatory cytokine IL-18 in brain-to immune cross-talk and
in neuropathological conditions. The data suggests that IL-18 may be a key
mediator, implicated in the communication between the immune and the
central nervous systems, with potential effects on cognitive and behavioral
functions.
Moreover, the altered modulation of the IL-18 system both in patients at
high risk of developing AD and in young SCZ subjects puts forth the notion
that IL-18 may intervene early in connecting IS with CNS by means of
inflammatory functions which would impact on the pathophysiological
processes underlying neurodegenerative and psychotic disturbances. These
findings confirm the need for further elucidation on the role of IL-18 in
CNS pathological conditions, with the aim of identifying innovative
diagnostic and therapeutic procedures for these devastating diseases.
Additional information
Dottorato di ricerca in Genetica e biologia cellulare
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