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Inflammation and atherosclerosis

Inflammation and atherosclerosis. Immune cells dominate early lesions Immune effector molecules accelerate lesion progression Activation of inflammation elicits acute coronary syndromes

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Inflammation and atherosclerosis

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  1. Inflammation and atherosclerosis • Immune cells dominate early lesions • Immune effector molecules accelerate lesion progression • Activation of inflammation elicits acute coronary syndromes • Atherosclerosis is an inflammatory disease in which immune mechanisms interact with metabolic risk factors to initiate, propagate and activate lesions in the arterial wall

  2. The numbers • CAD causes 38% of all deaths in North America • Most common cause of death in men under 65 y.o. and second most common cause of women • Dispite advances in control of hypercholesterolemia (statins),CVD expected to be the main cause of death globally over the next 15 years due to rapidly increasing prevalence of obesity and diabetes

  3. Pathogenesis of coronary artery thrombosis

  4. Cellular players in atherogenesis and plaque rupture

  5. The early lesion: modified lipoproteins and foam cell formation

  6. Role of macrophages • MCSF induces monocytes entering lesion to differentiate into macrophages • Macrophage differentiation associated with TLRs and scavenger receptors • MCSF/apoE KO shows reduced atherosclerosis • Scavenger receptors bind bacterial endotoxins, apoptotic cells and oxLDL • SR/apoE KOs show reduced atherosclerosis

  7. The macrophage as an inflammatory mediator

  8. TNF-R IL-1R IFN-gR Toll-like MAPKINASE NFkB JAK/STAT IRF GENES Inflammation, Anti-Microbial Response, Apoptosis, …

  9. TLR receptors and atherosclerosis • 10 family members • Recognize pathogen associated molecular patterns (e.g. LPS, dsRNA) as well as oxLDL, HSP60 etc. • Initiate signaling cascades leading to production of inflammatory cytokines, proteases, reactive oxygen species • In addition to macrophages, expressed by dendritic cells, mast cells, endothelial cells

  10. Macrophage-T cell interactions in atherosclerosis

  11. T cells and atherosclerosis • Immune cells patrol tissues in search of antigen • T cell infiltrate is common feature of atherosclerotic lesions • Predominantly CD4+ cells, recognize antigen/MHC II • CD4+ T cells reactive to oxLDL, HSP60, bacterial products detected in human lesions • NK cells present in early lesions, recognize lipid antigens • NK activation increases athero in apoE KO mice

  12. T cell responses • Th1 response activates macrophages and functions in the defense against intracellular pathogens • Th2 response elicits allergic inflammation • Atherosclerotic lesions contains cytokines that promote Th1 responses • Activated Th1 effector cells in lesions produce macrophage activating cytokine IFNg • IFNg improves efficiency of ag presentation and augments synthesis of TNFa and IL-1 • IFNg, TNFa and IL-1 in turn stimulate production of many other inflammatory mediators • apoE mice lacking IFNg or downstream mediators such as IL-18 or T-bet show reduced athero

  13. Anti-inflammatory factors and atherosclerosis • Anti-inflammatory factors such as TGFb and IL-10 are protective • IL-10 KO increases athero in mice and exacerbates thrombosis • Abrogation of TGF signaling in T cells leads to large unstable atherosclerotic lesions

  14. Immune cells and plaque rupture • Preferentially occurs where fibrous cap is thin • Active immune cells are abundant at site of rupture • Immune cells produce inflammatory molecules and proteolytic enzymes that weaken cap, activate cells in the core and transform stable plaque into vulnerable, leading to plaque rupture • MMPs likely to play important roles

  15. Systemic inflammatory markers in atherosclerosis

  16. Systemic indicators of inflammation • Inflammatory process in lesions may lead to increased plasma levels of cytokines and acute phase proteins • CRP and IL-6 are elevated in patients with unstable angina and MI • Levels correlate with prognosis

  17. IkB NF-B TLR-3/4 MyD88“Dependent” MyD88“Independent” TANK NEMO IKK-1 IKK-2 TBK-1 IKKi IRF-3 Antiviral Response InflammatoryResponse

  18. MyD88/apoE KO mice show reduced athero

  19. MyD88/apoE Ko mice show reduced chemokine expression

  20. MyD88/apoE KO macs show reduced chemokine expression and recruitment in response to inflammatory cytokines

  21. Links between infection and atherosclerosis • Unlikely to be caused by single organism • Diverse pathogens have been detected within lesions • Bacteria and viruses accelerate athero in murine models

  22. Potential mechanisms • Stimulation of inflammatory cytokines • Alteration of adhesion molecule expression ? Lipid metabolism ?

  23. oxLDL CD36 cholesterol CE Inflammatory stimuli ABCA1 LPS, IL-1b, TNFa oxysterol RXR LXR IL-1R TOLL4 TNFR CHOLESTEROL EFFLUX INFLAMMATION  PLTP  ABCAI  iNOS  IL-1b  ApoE/CII  LPL  IL-6 COX2  MMP9 MACROPHAGE

  24. p < 0.005 Synthetic LXR agonist reduces atherosclerosis inLDLR-/- and apoE-/- mice LDLR-/- Aortic Sections ApoE-/- Aortic Sections 300000 p < 0.005 250000 250000 200000 200000 197870 Lesion area (mM2/section) Lesion area (mM2/section) 150000 150000 134470 136610 100000 100000 70621 50000 50000 0 0 vehicle GW3965 high fat + GW3965 Joseph et al. PNAS 2002

  25. Loss of bone marrow LXR expression accelerates athero Aortic Lesion Coverage (%) C57Bl6 BMT * LXRab -/- BMT * apoE -/- BMT 0.0 2.5 5.0 7.5 Tangirala et al. PNAS 2002

  26. Bacterial or viral infection blocks expression of LXR target genes in macrophages Antonio Castrillo, Sean Joseph +/- Influenza A +/- E. coli Infl A + GW E. Coli + GW E. Coli + T Infl A + T GW3965 GW3965 T1317 Infl A E. Coli T1317 ctrl ctrl ABCA1 ABCA1 ABCG1 apoE FAS SREBP-1c MX-1 FAS IFN-b iNOS 36B4 36B4 Castrillo et al., Molecular Cell 2003

  27. TLR3 and TLR4 ligands inhibit cholesterol efflux from macrophages Cholesterol efflux 14 Ctrl 12 LXR ligand 10 * 8 apoAI-dependent efflux (%) 6 ** 4 * ** 2 0 Ctrl Ctrl LTA LTA TNFa TNFa Lipid A Lipid A Poly IC Poly IC

  28. Activation of TLR3 inhibits LXR signaling in vivo Aorta Spleen 11 ABCA1 ABCA1 5 vehicle 9 * * 7 mRNA Poly IC mRNA 3 5 3 GW3965 * 1 1 Both apoE apoE 3 4 * 3 mRNA mRNA 2 * 2 1 1 19 5 ABCG1 ABCG1 * 17 * mRNA 13 3 mRNA 9 5 1 1 7 IFN- IFN- 500 5 mRNA mRNA 300 3 100 1 400 IP-10 IP-10 50 300 mRNA mRNA 30 200 100 10 0 Poly IC Poly IC Poly IC Poly IC Vehicle Vehicle Vehicle Vehicle

  29. TLR-LXR crosstalk: potential implications for atherosclerosis virus cholesterol efflux bacteria other signals C C TLR-3/4 ABCA1 ? Foam cell formation  Foam cell formation C C C TANK C TBK-1 IKKi IRF-3 LXR RXR ABCA1, ABCG1, apoE

  30. Immunization with pneumococus induces oxLDL-specific IgM

  31. Immunization with pneumococus induces oxLDL-specific IgM s. pneumo s. pneumo + s. pneumo block s. pneumo + oxLDL block E06 (ox PL)

  32. Plasma from mice immunized with pneumococus inhibits macrophage binding of oxLDL

  33. Immunization with pneumococus reduces atherosclerosis in LDLR-/- mice

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