1. Dendritic Cells Overexpressing SOCS2
Reduce Atherosclerosis Development
Vanessa Frodermann
Division of Biopharmaceutics, Leiden/Academic Center for Drug Research,
Leiden University, Leiden, The Netherlands

2. Dendritic cells in atherosclerosis
CCR7
Tolerogenic DC,
induce Ag-specific
Treg or
T cell anergy
15 March 2013
Hansson GK & Hermansson A, Nat. Immunol. 2011

3. Cytokine signaling in dendritic cells is modulated by SOCS proteins
Suppressors of Cytokine Signaling are
negative feedback inhibitors of the JAK-STAT pathway
Induced by cytokines, LPS, statins etc.
Can bind other SOCS and target them for degradation
TLR
JAK
cytokines
SOCS
STAT
SOCS
SOCS
15 March 2013

4. SOCS2 deficient mice Gigantism due to increased GH signaling
(Metcalf D et al. Nature. 2000)
Increased pro-inflammatory cytokines
(Zadjali et al. FASEB. 2012)
More pro-inflammatory cells:
more Th2, less Treg
(Knosp CA et al. J Exp Med. 2011; J Immunol )
More M1 macrophages
(Spence et al. Immunity 2013)
15 March 2013

5. SOCS2 in dendritic cells
SOCS2 is induced by TLR ligands for negative feedback
(Posselt et al., J Immunol 2011; McBerry et al., PLoS One 2012)
Silencing of SOCS2 in DCs enhances IL-23 expression, resulting in more pro-inflammatory Th17
(Schwarz et al., Immunobiology 2012)
15 March 2013

6. Hypothesis SOCS2 Lentiviral overexpression of SOCS2
Pro-inflammatory
Cytokines,
Th17/ Th1
Anti-inflammatory
Cytokines,
Treg
SOCS2
Lentiviral overexpression of SOCS2
in dendritic cells reduces atherosclerosis.
15 March 2013

7. SOCS2-overexpressing dendritic cells are less inflammatory upon TLR4 ligation
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*P<0.05,**P<0.01,***P<0.001

8. SOCS2-overexpressing dendritic cells are semi-mature
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9. * 3 x i.v. injection of 1.5 x 106 dendritic cells
Effect of adoptive transfer of SOCS2-overexpressing dendritic cells on atherosclerosis * * *
Western-type diet
weeks
♂ LDLr-/-
10-12 weeks
* 3 x i.v. injection of 1.5 x 106 dendritic cells
PBS
LV-empty
LV-SOCS2
15 March 2013

10. Transfer of SOCS2- dendritic cells induces Treg and less Th1 cells
Trend to decreased Th17 and Th2.
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***P<0.001

11. Transfer of SOCS2- dendritic cells reduces T cell proliferation
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**P<0.01,***P<0.001

12. Reduced lesion formation
PBS
LV-empty
LV-SOCS2
No difference observed in collagen and monocyte/macrophage content.
15 March 2013
*P<0.05

13. SOCS2 DC decrease lesion formation
Inhibition of differentiation
and proliferation
Migration to LNs Th
Th0
Tolerogenic DC:
High migratory capacity
High co-stimulation
High Ag-presentation
Anti-inflammatory cytokines
CCR7
Therefore SOCS2-overexpression or induction in DCs can increase their treatment potential for atherosclerosis
SOCS2
Treg
IL-10
TGF-β
Treg induction
15 March 2013

14. Acknowledgments Peter v. Santbrink Saskia de Jager Ilze Bot
Miranda van Eck
Reeni Hildebrand
Erik van Kampen
Menno Hoekstra
Anouk Wezel
Max Lagraauw
Suzanne Korporaal
Daniël van der Velden
Thomas van der Heijden
Ronald van der Sluis
Thijs Zweers
Marco van der Stoep
Baoyan Ren
Division of Biopharmaceutics, LACDR, Leiden University
Peter v. Santbrink
Saskia de Jager
Ilze Bot
Gijs van Puijvelde
Amanda Foks
Johan Kuiper
15 March 2013