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