Dendritic Cells Overexpressing SOCS2

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

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

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

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. 2013 ) More M1 macrophages (Spence et al. Immunity 2013) 15 March 2013

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

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

SOCS2-overexpressing dendritic cells are less inflammatory upon TLR4 ligation 15 March 2013 *P<0.05,**P<0.01,***P<0.001

SOCS2-overexpressing dendritic cells are semi-mature 15 March 2013

* 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 -1 0 2 4 6 8 10 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

Transfer of SOCS2- dendritic cells induces Treg and less Th1 cells Trend to decreased Th17 and Th2. 15 March 2013 ***P<0.001

Transfer of SOCS2- dendritic cells reduces T cell proliferation 15 March 2013 **P<0.01,***P<0.001

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

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

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