Immune-Mediated Mechanismsof Atherosclerosis

Ziad Mallat, MD, PhD

Department of Medicine, University of Cambridge,Cambridge, UK

Inserm U970

British HeartFoundation

Hanson GK.N Engl J Med 2005

Effect of Subendothelial Retention of Atherogenic Lipoproteins on Atherosclerosis

Skalen et al. Nature, 2002;417:750-754.

Proteoglycan-binding-defective LDL

Wild type-control LDL

Crucial role of monocytes/macrophages in atherosclerosis

(Smith et al, PNAS, 1995)

M-CSF deficiency inhibits plaque formation (Smith, PNAS 1995)

Lesi

on s

ize

um2

M-CSF deficiency inhibits plaque formation (Smith, PNAS 1995)

Monocyte subsets

Woollard KJ, Nature Rev Cardiol 2010

classical

nonclassical

Hannah RN, Nat Immunol 2011

Cros J et al, Immunity 2010

Carlin LM et al, Cell 2013

CX3CR1+/CD16+Ly6C(lo)

CCR2+/CD16–Ly6C(hi)

Charo I, NEJM 2006

Classical monocytesCCR2hi

CX3CR1lo

CCR5+

Non classical monocytesCCR2lo

CX3CR1hi

CCR5+

Anti-CCR5

(Combadière et al, Circulation 2008)

Additive roles for monocyte subsets in atherosclerosis

MacrophageDendritic Cell

MacrophageDendritic Cell

CX3CL1CX3CR1+Ly6C(lo)

CCL2CCR2+Ly6C(hi)

Chemokines and Atherosclerosis

Control of Monocyte Numberin Blood and Bone Marrow

Apoe—/—

7/4

Ly-6G

8.6% 5.7%

Apoe—/—/Ccl2—/—/ Cx3cr1—/—

7/4

Ly-6G

C57Bl/6 Ccl2—/—/ Cx3cr1—/—

12 3

2.6%

2.0%

1.3%

0.7%CCL2/CCR2

CX3CL1/CX3CR1

Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor

CCR2 (Serbina MV, Nat Immunol 2006)

Suzuki H et al, Nature 1997

Hanson GK.N Engl J Med 2005

Spann NJ et al. Cell 2012

Pro & Anti-Atherogenic Signaling Pathways

Tedgui & Mallat, Physiol Rev 2006

Pro & Anti-Atherogenic Signaling Pathways

Tedgui & Mallat, Physiol Rev 2006

Lutgens E et al,J Exp Med 2010

Lahoute C et al., Nat Rev Cardiol 2011

2006

2009

2006

Choi JH et al., 2006

Koltsova EK et al.,JCI 2012

Lahoute C et al., Nat Rev Cardiol 2011

Recruitment and Activation of Th1 in Atherosclerosis

Hansson & Libby, Nat Rev Immunol 2006

Lahoute C et al., Nat Rev Cardiol 2011

Th2

STAT6GATA-3

IL-5

IL-33IL-13

OX40L OX40

IL-25IL-13IL-6 CCL2

IL-4

B1 cell

oxLDL-IgM

endothelial activation

VSMC

M2 macrophage

Lahoute C & Mallat Z, 2011

Potential Role of Th2 Cells in Atherosclerosis

Cardilo-Reis L et al.,EMBO Mol Med 2012

Binder CJ et al.,JCI 2004

Miller AM et al.,JEM 2008

Pro & Anti-Atherogenic Signaling Pathways

Tedgui & Mallat, Physiol Rev 2006

Hanson GK.N Engl J Med 2005

Ait-Oufella et al. 2006

nTreg and TGF-β

Mallat et al. 2003

Tr1 cells: IL-10

Regulatory T cells Control Atherosclerosis

IL10TGFβ

Akbar AN et al., Nat Rev Immunol, 2007

Cont CD28KO+TregCD28KO

Lesion size (x105 m2)

*

Ait-Oufella et al. Nat Med 2006

Lahoute C et al., Nat Rev Cardiol 2011

Choi J-H et al., Immunity 2011

Choi J-H et al., Immunity 2011

Weber C et al.,

JCI 2011

Maintenance of tolerance

Th1

Th2

Treg

Treg

Mac.

IL10TGFb

IFNg

Treg

Th2 Th1

IL10TGFb

Atherosclerotic plaque

Lymph node

Regulation of inflammation

SMC SMCECEC

Pathogenic immunity

Mallat et al., Physiol Rev 2006; J Lipid Res 2008

oxLDL, HSP…

Pathogenic DC IFNg

Tolerogenic DC Apoptotic debris

Mfge8, Mertkdependent clearance

TLRs,IL12/IL18…

IL10TGFb

IL4

IL12

Compromised Treg induction/survival in inflammatory site

Savill J et al.,Nat Rev Immunol 2002

b

Mfge8+/+ Mfge8/Mfge8/

d Percentacellular core

Mfge8+/+ Mfge8/

**Microparticle level(x103/l plasma)

Mfge8+/+ Mfge8/

**e

Lesion size(x105 m2)

a

Mfge8+/+ Mfge8/ Mfge8+/+ Mfge8/

**

c

Caspase-3

Ait-Oufella et al., Circulation 2007

Treg cell

Foxp3IL-10TGF-b

Apoptotic bodies

APC TolerogenicAPC

TGF-bIL-10

PRRMfge8-

dependentclearance

TGF-bIL-10

Atherosclerosis

Th1Th2Th17

IL-6IL-12IL-23

IFNg

IL-4IL-17

Mature APC

PRR(Tlr4…)

Pathogenic T cell

No Mfge8(defectiveclearance)

Free Cholesterol

αvβ3

Mfge8 Inhibits inflammasome-induced IL1β production

Deroide N, Li X et al., J Clin Invest 2013

Deroide N, Li X et al., J Clin Invest 2013

Lahoute C et al., Nat Rev Cardiol 2011

Pro & Anti-Atherogenic Signaling Pathways

Tedgui & Mallat, Physiol Rev 2006

Levy DE & Loomis CA, NEJM 2007

Taleb et al. 2010

University of CambridgeBritish Heart Foundation

Andy SAGEDeirdre MURPHY

Lauren BAKERJames HARRISONLeanne MASTERS

Xuan LICéline LOINARDFernanda SCHREIBERNada SALEH

Inserm U970Alain TEDGUIHafid AIT-OUFELLAOlivier HERBINPatrick BRUNEVAL

Jean-SébastienSILVESTREYasmine ZOUGGARI

CeMM, Medical Universityof Vienna, AustriaChristoph J. BINDER

AP-HP, Pierre et Marie Curie UniversityTabassome SIMON

Duke University, USAThomas F. TEDDER

University of Utrecht,The NetherlandsGerard PASTERKAMP

UCSF, USAIsrael F. CHARO

0200

400

600

800

1000

1200

1400

Control SOCS3 -/-

Tota

l cho

lest

erol

(m

g/dl

)

Taleb et al. J Exp Med, 2009;206:2067-2077

Neutralization of IL17 Abrogates theAthero-Protective Effect of T Cell-Specific SOCS3 Deletion

Taleb et al. J Exp Med 2009;206:2067-2077

IL-17 reduces atherosclerosis in LDLr-/- mice

Taleb et al. 2010

Lahoute C et al., Nat Rev Cardiol 2011

Latz E et al,Nat Rev Immunol 2013