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Transcript
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 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 Pathogenesis of coronary artery thrombosis Cellular players in atherogenesis and plaque rupture The early lesion: modified lipoproteins and foam cell formation 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 The macrophage as an inflammatory mediator TNF-R IL-1R IFN-gR Toll-like NFkB MAP KINASE JAK/STAT IRF GENES Inflammation, Anti-Microbial Response, Apoptosis, … 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 Macrophage-T cell interactions in atherosclerosis 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 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 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 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 Systemic inflammatory markers in atherosclerosis 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 TLR-3/4 MyD88 “Independent” MyD88 “Dependent” TANK NEMO TBK-1 IKKi IKK-1 IKK-2 IkB IRF-3 NF-kB Antiviral Response Inflammatory Response MyD88/apoE KO mice show reduced athero MyD88/apoE Ko mice show reduced chemokine expression MyD88/apoE KO macs show reduced chemokine expression and recruitment in response to inflammatory cytokines 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 Potential mechanisms • Stimulation of inflammatory cytokines • Alteration of adhesion molecule expression ? Lipid metabolism ? oxLDL CD36 cholesterol CE Inflammatory stimuli ABCA1 LPS, IL-1b, TNFa oxysterol IL-1R RXR LXR TOLL4 TNFR INFLAMMATION iNOS IL-1b IL-6 COX2 MMP9 CHOLESTEROL EFFLUX PLTP ABCAI ApoE/CII LPL MACROPHAGE Synthetic LXR agonist reduces atherosclerosis inLDLR-/- and apoE-/- mice LDLR-/- Aortic Sections ApoE-/- Aortic Sections 300000 p < 0.005 250000 250000 200000 197870 150000 136610 100000 Lesion area (mM2/section) Lesion area (mM2/section) p < 0.005 200000 150000 134470 100000 70621 50000 50000 0 0 high fat Joseph et al. PNAS 2002 + GW3965 vehicle GW3965 Loss of bone marrow LXR expression accelerates athero Aortic Lesion Coverage (%) * C57Bl6 BMT * LXRab -/BMT apoE -/BMT 7.5 5.0 2.5 0.0 Tangirala et al. PNAS 2002 Bacterial or viral infection blocks expression of LXR target genes in macrophages ABCA1 ABCA1 apoE ABCG1 SREBP-1c FAS iNOS 36B4 Castrillo et al., Molecular Cell 2003 FAS MX-1 IFN-b 36B4 Infl A + T Infl A + GW Infl A T1317 GW3965 +/- Influenza A ctrl E. Coli + T E. Coli T1317 GW3965 ctrl +/- E. coli E. Coli + GW Antonio Castrillo, Sean Joseph TLR3 and TLR4 ligands inhibit cholesterol efflux from macrophages Cholesterol efflux apoAI-dependent efflux (%) 14 12 Ctrl LXR ligand 10 8 * 6 ** 4 * 2 0 ** Activation of TLR3 inhibits LXR signaling in vivo Aorta Spleen 11 ABCA1 7 5 * 5 3 1 mRNA mRNA 9 ABCA1 vehicle * 3 1 Poly IC GW3965 * Both 3 mRNA mRNA 4 apoE 3 2 * 1 mRNA 17 * 13 9 5 * 2 1 5 ABCG1 mRNA 19 apoE ABCG1 * 3 1 1 IFN-b 5 500 mRNA mRNA 7 3 200 100 0 IP-10 mRNA mRNA 300 300 100 1 400 IFN-b 50 30 10 IP-10 TLR-LXR crosstalk: potential implications for atherosclerosis virus cholesterol efflux bacteri a other signals C TLR-3/4 ? C ABCA1 Foam cell formation C C TANK C C TBK-1IKKi IRF-3 LXR RXR ABCA1, ABCG1, apoE Immunization with pneumococus induces oxLDL-specific IgM Immunization with pneumococus induces oxLDL-specific IgM s. pneumo s. pneumo + s. pneumo block s. pneumo + oxLDL block E06 (ox PL) Plasma from mice immunized with pneumococus inhibits macrophage binding of oxLDL Immunization with pneumococus reduces atherosclerosis in LDLR-/- mice