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Dendritic Cells Overexpressing SOCS2 Reduce Atherosclerosis Development Vanessa Frodermann

Dendritic Cells Overexpressing SOCS2 Reduce Atherosclerosis Development Vanessa Frodermann Division of Biopharmaceutics, Leiden/Academic Center for Drug Research, Leiden University, Leiden, The Netherlands. Tolerogenic DC, induce Ag-specific Treg or T cell anergy.

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Dendritic Cells Overexpressing SOCS2 Reduce Atherosclerosis Development Vanessa Frodermann

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

  3. JAK JAK 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 cytokines SOCS STAT SOCS SOCS

  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) • Morepro-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)

  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)

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

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

  8. SOCS2-overexpressing dendritic cells are semi-mature

  9. 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

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

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

  12. Reduced lesion formation PBS LV-empty LV-SOCS2 No difference observed in collagen and monocyte/macrophage content. *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 SOCS2 Treg IL-10 TGF-β Treg induction

  14. Acknowledgments • 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

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