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An Analysis of IL-33 and its Decoy
Receptor sST2 in Alzheimer’s
Disease and Mild Cognitive
Impairment Patients
Laboratory of Molecular Medicine and
Biotechnology, Don Carlo Gnocchi Foundation -
ONLUS, IRCCS Milan, Italy
4th NeuroMi International Meeting – Milan, Italy November 21st 2018
Federica Piancone, PhD
ALZHEIMER’S DISEASE
Neurodegenerative disease
characterized by neuronal
cellular loss and progressive
dementia
Symptoms:
• Memory loss
• Confusion with time or place
• Changes in mood and
personality
Neuropathology:
•Extracellular accumulation of
amyloid β (Aβ) (plaques)
•Formation of neurofibrillary
tangles inside neurons (tau)
• Damage of brain cells and its
connection
ALZHEIMER’S DISEASE NEUROINFLAMMATION
IL-1b
Impaired β-amyloid
clearance
Microglia activation
Production of pro-
inflammatory cytokines and
chemokines
Peripheral immune cells
recruitment
Peripheral immune cell activation
βA- mediated in AD:
• Increase of inflammatory
monocytes in AD
•Th17 and Th9 activation
in AD
• Activation of NLRP3
inflammasome in AD
with production of IL-1β
and IL-18
• Impairment of
inhibitory PD-1/PD-L1
pathway in AD
• Loss of PD1 neg Treg
cells in AD
IL-33/ ST2
IL-33
Dual function:
• nuclear factor with
transcriptional regulatory
functions (gene expression
NFKB- mediated interfering)
• extracellular protein with
cytokine properties
Hardman and Ogg, 2016, modified.
IL-6
NLRP3
IL-1β
ST2
Endogenous ligand for IL-33
Two isoforms:
• soluble ST2 (sST2): inhibits the
IL-33/ST2 signaling (decoy receptor)
• transmembrane (ST2L): mediates
effector function of IL-33
IL-33/ ST2
ST2L
is expressed on different immune
cells and its binding with IL-33
induces anti-inflammatory or pro-
inflammatory responsesMehraj, 2016
Miller, 2011 , modified
IL-33
is released by necrotic or apoptotic
processes in active or inactive
form, respectivelyInactive form
Active form
AIM
The possible role of IL-33 in AD has not been clarified
IL-33 production is decreased
in LPS+βA- stimulated
monocytes of AD
IL-33 production is decreased in
LPS+βA- stimulated monocytes
of AD converter
IL-33 administration in
APP/PS1 mice ameliorates AD
symptoms, polarizes
monocytes to anti-
inflammatory phenotype
High concentration of IL-33 in
neuropathological lesions of
AD brain
TO EVALUATE THE ROLE OF
THE ST2/ IL-33 AXIS
IN AD-ASSOCIATED INFLAMMATION
AIM
MATHERIALS AND METHODS
Subjects enrollment:
Neurology Department of the Don Gnocchi Foundation
IRCCS Ca’ Granda Ospedale Maggiore Policlinico
AD and MCI diagnosis
Clinical diagnosis was performed according to NINCDS-ADRDA work group criteria,
DMS III-R and Petersen.
CSF, serum, whole blood collection
All individuals enrolled in the study provided written informed consent according to a protocol approved by a local ethics committee of the Don Gnocchi Foundation before the admission to the study
30 Alzheimer’s Disease patients
(AD)
10 males, 20 females
age range: 54-88 years
30 Mild Cognitive Impairment patients
(MCI)
8 males, 22 females
age range: 63-84 years
27 Healthy controls
(HC)
age- and- sex matched
pg
/ml
IL-33 SERUM
AD MCI HC
0.02
0.04
pg
/ml
IL-33 CSF
AD MCI HC
0.009
0.01
AD MCI HC ADc-IL-33 f-IL-33Marker
32kDa
25kDa
22kDa
AD MCI HC
IL-33 SERUM IL-33 CSF
RESULTS
pg
/ml
sST2 SERUM
AD MCI HC
0.02
0.01
• Full lenght form of IL-33 is detected in all individuals, except
two AD patients
• IL-33 is significantly decreased in serum and CSF of AD and
MCI compared to HC
• sST2 is significantly increased in serum of AD and MCI
compared to HC
RESULTSp
g/m
l
IL-1b SERUM
AD MCI HC
0.01
0.01
IL-1b CSF
AD MCI HC
0.02
0.01
pg
/ml
IL-6 SERUM
AD MCI HC
pg
/ml
IL-10 SERUM
AD MCI HC
0.04
0.04
pg
/ml
AD MCI HC
IL-6 CSFp
g/m
l
• IL-1β is significanlty increased in serum and CSF of AD and
MCI compared to HC
• IL-10 is significantly increased in serum of HC compared to
AD and MCI
AD MCI HC
IL-10 CSF
pg
/ml
RESULTS
LPS+ Ab42 LPS+Ab42+
IL-33
pg
/ml
IL-1b
LPS+Ab42 LPS+Ab42+IL-33
pg
/ml
IL-6
LPS+Ab42 LPS+Ab42+IL-33
pg
/ml
IL-10
In vitro addition of IL-33 in LPS+Aβ42-stimulated PBMC
resulted in:
• a reduced generation of IL-1β and IL-6 in all individuals;
• an increased production of IL-10 in HC alone.
CONCLUSIONS
THESE DATA COULD SUPPORT THE PROTECTIVE
ROLE OF IL-33 IN THE PATHOLOGY
AND IT COULD SUGGEST IL-33 AS A NOVEL
THERAPEUTIC APPROACH
The decrease of IL-33 levels and the increase of its
decoy receptor sST2 characterize AD and MCI
individuals suggesting that
impaired IL-33/ ST2 signaling may contribute
to the pathogenesis of AD
Prof. Mario Clerici
Dr. Marina Saresella
Sig. Ivana Marventano
Dr. Francesca La Rosa
Laboratory of Molecular
Medicine and Biotechnology
Aknowledgment
Thank you