Matthias Nahrendorf

HARVARD

MEDICAL

SCHOOL

MGH Center for Systems Biology http://csb.mgh.harvard.edu/investigator/matthias_nahrendorf

The Role of the Various Monocyte Types in Athero-

thrombotic Disease

Protective vs. Detrimental Effects and Therapeutic Implications

MedicineNet.com

Good healing

Bad healing

50% chance of death in next

year

Good prognosis

Circulation. 1993 Mar;87(3):755-63

Healing following myocardial infarction matters

Monocyte/macrophage heterogeneity

in myocardial infarction

Swirski & Nahrendorf, Science 2013;339:161-6

Monocytes/macrophages in

atherosclerosis

Swirski & Nahrendorf, Science 2013;339:161-6

Blood monocytosis

Recruitment

Ly-6Chi

EF

LV dilation

Infarct expansion

Protease activity

Inflammatory

cyto/chemokines

Collagen

synthesis

Resolution of

inflammation

Atherosclerosis

Heart Failure

Impair

ed

in

farc

t he

alin

g a

fte

r pla

qu

e r

uptu

re

(e.g. MPO, TNF-α)

(e.g. MMPs,

cathepsins)

(e.g. reduced TGF-β)

Circulation 2010; 121:2437

Inflammatory monocytes

Qu

alit

y o

f h

ea

ling

1. Swirski & Nahrendorf, Science 2009

2. van Amerongen, Am J Pathol 2007

3. Nahrendorf & Swirski, JEM 2009

apoE-/- with blood monocytosis7

patients with high CD14+CD16– blood levels5

patients with blood monocytosis6

4. Roberts, Circulation 1976

5. Tsujioka, JACC 2009

6. Maekawa, JACC 2002

7. Panizzi, JACC 2009

splenectomized mice1

patients on steroids4

monocyte– depleted mice2,3

vertex (coronary ligation in healthy wild-type mice)3

Circulation 2010; 121:2437

Is there a window of therapeutic opportunity

to intervene on inflammation post MI?

White blood cell count associates with in-hospital mortality in infarct patients (n = 115,000)

Coller et al., ATVB 2005;25:658-670

Leukocyte count

Mo

rtality

(%

)

0

6

12

18 ****

No

MI

d1

d3

d7

MI

d5

% o

f B

rdU

+ H

SC

0.0

0.2

0.4

SU

V

No MI MI

**

MI No MI

Long-term

hematopoietic

stem cell

Short-term

hematopoietic

stem cell

Common

myeloid

progenitor

Granulocyte

Macrophage

progenitor

Macrophage Monocyte

Macrophage

dendritic cell

progenitor

Bone marrow Blood

Spleen

Destination

tissue

18F-FLT PET FACS Bone Marrow

Dutta et al., Cell Stem Cell 2015

Before After

Release

Ang II triggers release of monocytes into peripheral

blood

The spleen is a reservoir for monocytes after MI

Expression profile

Monocytes in Blood

Monocyte

s in

Sple

en

splenic monocytes resemble blood

monocytes (99.998%)

Behavioral activity Organization

splenic monocytes cluster in the

subcapsular red pulp Inflammation mobilizes monocytes in vivo

Consequence

– Spleen + Spleen

Released splenic monocytes participate

in inflammation

Pre injury Post injury

vessel parenchyma

Relocation

The spleen contributes monocytes in infarct

0

3

6 Pre MI + Spleen – Spleen

*

* Ly-6

Chi m

on

ocyte

s/m

g

tissu

e (

10

4)

no

MI

Day post MI

0.5 1

Science 2009; 325:612

Incre

ase

in

pro

tea

se

activity (

pm

ol)

MI

No M

I

Week 0 Week 3

0

15

30 *

MI enhances protease activity in plaque

No MI MI

4

7

Ex v

ivo T

BR

FR

I

1

*

Week 3

Dutta/Courties et al., Nature 2012;487:325-9

Age (in weeks)

0

3

6

20 30

Ly-6

Chig

h m

onocyte

s (

10

3)

/ aort

a

MI

No MI

MI enhances monocyte/macrophage

numbers in plaque

CD

11b

+ a

rea (

mm

2)

0

0.1

*

0

0.4 P

laque s

ize (

mm

2)

* 0.2

0.2

0.6

MI No MI

Dutta/Courties et al., Nature 2012;487:325-9

MI enhances atherosclerosis

Swirski & Nahrendorf, Science 2013;339:161-6

Tawakol et al., iJACC 2015

18F-FDG uptake increases in atheroma, bone

marrow, and spleen during acute MI

Danger signals: IL-1β Sager / Dutta

Heart

200

5

0

IL-1

β m

RN

A

10

**** **** ** ***

750

0

1500

Infa

rct IL

-1β

(pg/m

l)

3 days

3 days

3 days

14d

14d

14d

FACS

MI

WT

FACS

MI

FACS

WT

WT

WT

WT

WT

WT

WT

WT

WT

steady state

non-infarcted

parabiont

non-infarcted

IL1R1-/- parabiont

no MI 24h 72h

MI

no MI 24h 72h

MI

Blo

od

IL-1

β (

pg/m

l)

125

0

250 ** ***

no MI 24h 72h

MI

Marr

ow

IL-1

β (

pg/m

l)

100

0

200 **

no MI 24h 72h

MI

C-k

it

Sca-1

CD

48

CD150

CD150

Brd

U

IL1

R1

-/-

IL1

R1

-/-

ste

ad

y s

tate

no

n-infa

rcte

d

pa

rab

iont

no

n-in

farc

ted p

ara

bio

nt

% o

f B

rdU

+ H

SC

s/f

em

ur

24

12

0

IL1

R1

-/-

Sager / Dutta

Sca-1

C-k

it

CD150

CD

48

no MI + Ctrl IgG

17.9 12.8 8.3

1.56 2.29 0.54

MI + Ctrl IgG MI + anti IL-1β

10

4 L

SK

s/fe

mu

r

3

6

0

*

% o

f B

rdU

+ H

SC

s/fe

mu

r 20

10

0

*

Brd

U

Sca-1

25.4 33.7 17.8 *

2.5

0

5

10

3H

SC

s/fe

mu

r

*

Anti IL-1β therapy modulates hematopoiesis

Sager / Dutta

neutr

ophils

(x10

3)/

mg infa

rct

Ly6c

hig

h m

onocyte

s

(x10

3)/

mg infa

rct

macro

phages

(x10

3)/

mg infa

rct

Ly6C

F4

/80

CD11b

Lin

eage

MI + Ctrl IgG MI + anti IL-1β

30

15

0

* 5

10

0

* 5

0

10

*

Ly6c

low m

onocyte

s

(x10

3)/

mg infa

rct

6

0

12

Anti IL-1β therapy mutes

inflammatory leukocytes during

myocardial infarction

Sager / Tricot / Wojtkiewicz

MI + anti IL-1β

7 d

aft

er

MI

MI + Ctrl IgG

infa

rct

pro

tease

activity (

pm

ol)

100

0

200

21 d

aft

er

MI

decre

ase in

LV

EF

(%

)

1 d

aft

er

MI

infa

rct

siz

e (

% o

f

myocard

ium

)

20

0

40

15

0

30

*

*

Anti IL-1β therapy improves LV function

post MI

Acknowledgements Ned Keliher

Maulik Majmudar

Gabriel Courties

Florian Leuschner

Partha Dutta

Hendrik Sager

Felix Hoyer

Gabriel Courties

Fanny Herrison

Yuxiang Ye

Yoshiko Iwamoto

Yuan Sun

Kamila Naxerova

Fil Swirski

Dan Anderson

Chares Lin

David Scadden

Marcelo Di Carli

David Sosnovik

Ahmed Tawakol

Willem Mulder

Zahi Fayad

Michael Moskowitz

Ralph Weissleder

Peter Libby

HARVARD

MEDICAL SCHOOL

csb.mgh.harvard.edu/nahrendorf

HHSN268201000044C, R01HL095629,

R01HL096576, R01HL114477,

R01HL117829