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1SY02-3 Innate immunity in atherosclerosis
4
1SY02
Monday September 29, 2003: Symposium Immunity and Inflammation in Atherosclerosis
scription of downstream target genes. In the enterohepatic system, these target genes include cytochrome P450s and other enzymes that catabolize the lipid, intracellular binding proteins that buffer the lipid in cells, and ATP-binding cassette transporters that move lipids out of cells. Our newest studies have shown that these lipid sensing receptors also play key roles in orchestrating the transport, storage, and metabolism of cholesterol, triglycerides, and free fatty acids in peripheral tissues, such kidney, muscle, adipose, lung, spleen, the immune system, and the central nervous system. The focus of our most recent studies in these tissues has been on the LXRs. Remarkably, in addition to maintaining cholesterol homeostasis, we have now shown that the LXRs are required for the body to respond properly to dietary fat. These studies point to a unique mechanism of action that involves a complex cross-talk with several metabolic pathways, and other nuclear receptors.
1SY02 IMMUNITY AND INFLAMMATION IN ATHEROSCLEROSIS
1SY02-4
B. Bottazzi, G. Peri, C. Garlanda, R. Latini, A. Maggioni, A. Mantovani. Mario Negri Institute, Milan, Italy The long pentraxin PTX3 was originally identified (cDNA and genomic, mouse and human) as an IL-1 inducible gene in endothelial cells. PTX3 is a prototypic long pentraxin consisting of a C terminal pentraxin domain (with similarity to C Reactive Protein, CRP, and Serum Amiloid P Component, SAP) coupled to an unrelated N terminal portion. Unlike CRP, produced in the liver, it is induced by inflammatory signals mainly in endothelial cells and macrophages. Recent data in gene targeted mice show that PTX3 is a unique soluble pattern recognition receptor playing a non redundant role in innate immunity and female fertility. PTX3 is produced in atherosclerotic lesions and levels increase in ischemic heart disorders. Recent results on the prognostic significance of PTX3 in acute myocardial infarction will be discussed. 1SY02-5
1SY02-1
Regulation of proatherosclerotic immunity
G.K. Hansson. Karolinska Institute, Sweden Atherosclerosis is accompanied by a local immune response in the plaque but its role in the pathogenesis of the disease is still unclear. Although one might expect that an (auto)immune response would be an aggravating factor, some of its consequences could be protective. Studies of human plaques and of lesion formation in apo E-0 mice show that CD4+ T cells and macrophages form an inflammatory infiltrate. Both cell types are activated and secrete proinflammatory cytokines. CD4+ cells respond immunospecifically to oxidized LDL, suggesting that oxidation induces antigenic epitopes on LDL and converts it to an autoantigen. The pathophysiological consequences of this response are probably mediated largely via cytokine secretion. Th1 cytokines dominate and promote vascular inflammation, which is proatherogenic as deduced fromcell transfer into immunodeficient apoE-0 x SCID mice. However, this is regulated by systemic immune activities involving B and T cells. Thus, spleen B cells develop atheroprotective immunity during the course of disease and transfer of such B cells can protect recipients against severe disease. Similarly, transfer of regulatory T cells may reduce disease in a murine model. Two immunoregulatory cytokines, interleukin-10 and transforming growth factor-beta, are key mediators of this atheroprotective immunity. Our data show that activation of immune regulatory loops dampen proatherosclerotic immunity and inflammation. The balance between proatherosclerotic and atheroprotective immunity may be an interesting target for future treatment of disease. 1SY02-3
Innate immunity in atherosclerosis
The long pentraxin PTX3: From innate immunity to ischemic heart disorders
Inflammatory activators in the acute coronary syndromes
P. Libby. Brigham and Women’s Hospital, USA Recently a combination of clinical and laboratory observations have transformed our understanding of the mechanisms underlying the acute coronary syndromes. Thrombosis on the substrate of a disrupted atheromatous plaque rather than a critical fixed stenosis causes most acute coronary events. The physical integrity of the plaque, notably of the extracellular matrix of the fibrous capsule overlying the atheroma’s thrombogenic lipid core, thus governs the most important clinical manifestations of atherosclerosis. Atheromata that have ruptured and caused fatal acute myocardial infarction usually have thin fibrous caps, and large lipid pools. Accumulating evidence implicates inflammation as a critical determinant of the stability of human atherosclerotic plaques. Plaques that rupture generally have more abundant leukocytic infiltrates than those considered stable. Patients with signs of inflammation measured in the peripheral blood have increased risk of future coronary events. Inflammatory mediators such as cytokines can influence several biological processes that regulate stability of the plaque’s fibrous cap, hence its resistance to rupture. Inflammatory cytokines such as interleukin-1, tumor necrosis factor (TNF), and the cell surface homologue of TNF-α known as CD-40 ligand can also elicit the expression by macrophages and smooth muscle cells of enzymes that can weaken the extracellular matrix. The role of inflammation in the biology of the acute coronary syndromes has clinical as well as pathophysiologic relevance. First, circulating levels of soluble forms of certain cytokines, particularly CD40 ligand, as well as downstream inflammatory markers such as C-reactive protein can predict prognosis of patients with acute coronary syndromes. Second, modulators of inflammation may have a role in the prevention and treatment of the thrombotic complications of atherosclerosis.
L. Curtiss. The Scripps Research Institute, Department of Immunology, La Jolla, CA, USA Atherosclerosis involves a chronically inflamed state of the vessel wall. In lesions, many indicators of inflammation are present including soluble inflammatory mediators such as cytokines and chemokines, inflammatory cells such as macrophages, and endothelial cells covering the lesion expressing an inflamed phenotype. Toll-like receptors (TLRs) are at the heart of inflammation initiated by the innate immune system. The TLRs and especially TLRs 2 and 4 are essential for detecting the presence of microbial pathogens. In the absence of TLR2 or TLR4, an effective innate immune response to infection does not develop in time to curb microbial growth and the host dies of bacteremia. In atherosclerosis, roles for TLRs are unknown. We took advantage of bone marrow transplant (BMT) technology to test the hypothesis that ablation of TLR4 or TLR2 responses in bone marrow-derived cells (BMDC) would alter lesion progression. BMT of cells from TLR2-/-, TLR4-/-, or MYD88-/- mice into lethally irradiated LDLR-/- mice yielded three sets of chimeric mice. After a 4-week period of recovery from the BMT procedure, the mice were fed a high fat diet (HFD) to induce rapid atherosclerotic lesion development. Mouse weights and plasma cholesterol levels were monitored after BMT. At 12 weeks post-BMT, the mice were sacrificed and lesion areas in their aortas and at the aortic sinus were assessed. The data indicate that TLR2-/- BMDC made no difference to the progression of atherosclerosis in the LDLR-/- mice. However, TLR4-/- or MyD88-/- BMDC permitted accelerated atherosclerotic lesion development inasmuch as these mice had significantly increased lesion areas. The data for TLR4 and MyD88 suggest that expression of these molecules in the BMDC is atheroprotective and suggest that a certain low level of TLR4 activation, perhaps initiated by endogenous agonists, leads to a beneficial lesion repair process. XIIIth International Symposium on Atherosclerosis, September 28–October 2, 2003, Kyoto, Japan
1SY02
Monday September 29, 2003: Symposium Immunity and Inflammation in Atherosclerosis
scription of downstream target genes. In the enterohepatic system, these target genes include cytochrome P450s and other enzymes that catabolize the lipid, intracellular binding proteins that buffer the lipid in cells, and ATP-binding cassette transporters that move lipids out of cells. Our newest studies have shown that these lipid sensing receptors also play key roles in orchestrating the transport, storage, and metabolism of cholesterol, triglycerides, and free fatty acids in peripheral tissues, such kidney, muscle, adipose, lung, spleen, the immune system, and the central nervous system. The focus of our most recent studies in these tissues has been on the LXRs. Remarkably, in addition to maintaining cholesterol homeostasis, we have now shown that the LXRs are required for the body to respond properly to dietary fat. These studies point to a unique mechanism of action that involves a complex cross-talk with several metabolic pathways, and other nuclear receptors.
1SY02 IMMUNITY AND INFLAMMATION IN ATHEROSCLEROSIS
1SY02-4
B. Bottazzi, G. Peri, C. Garlanda, R. Latini, A. Maggioni, A. Mantovani. Mario Negri Institute, Milan, Italy The long pentraxin PTX3 was originally identified (cDNA and genomic, mouse and human) as an IL-1 inducible gene in endothelial cells. PTX3 is a prototypic long pentraxin consisting of a C terminal pentraxin domain (with similarity to C Reactive Protein, CRP, and Serum Amiloid P Component, SAP) coupled to an unrelated N terminal portion. Unlike CRP, produced in the liver, it is induced by inflammatory signals mainly in endothelial cells and macrophages. Recent data in gene targeted mice show that PTX3 is a unique soluble pattern recognition receptor playing a non redundant role in innate immunity and female fertility. PTX3 is produced in atherosclerotic lesions and levels increase in ischemic heart disorders. Recent results on the prognostic significance of PTX3 in acute myocardial infarction will be discussed. 1SY02-5
1SY02-1
Regulation of proatherosclerotic immunity
G.K. Hansson. Karolinska Institute, Sweden Atherosclerosis is accompanied by a local immune response in the plaque but its role in the pathogenesis of the disease is still unclear. Although one might expect that an (auto)immune response would be an aggravating factor, some of its consequences could be protective. Studies of human plaques and of lesion formation in apo E-0 mice show that CD4+ T cells and macrophages form an inflammatory infiltrate. Both cell types are activated and secrete proinflammatory cytokines. CD4+ cells respond immunospecifically to oxidized LDL, suggesting that oxidation induces antigenic epitopes on LDL and converts it to an autoantigen. The pathophysiological consequences of this response are probably mediated largely via cytokine secretion. Th1 cytokines dominate and promote vascular inflammation, which is proatherogenic as deduced fromcell transfer into immunodeficient apoE-0 x SCID mice. However, this is regulated by systemic immune activities involving B and T cells. Thus, spleen B cells develop atheroprotective immunity during the course of disease and transfer of such B cells can protect recipients against severe disease. Similarly, transfer of regulatory T cells may reduce disease in a murine model. Two immunoregulatory cytokines, interleukin-10 and transforming growth factor-beta, are key mediators of this atheroprotective immunity. Our data show that activation of immune regulatory loops dampen proatherosclerotic immunity and inflammation. The balance between proatherosclerotic and atheroprotective immunity may be an interesting target for future treatment of disease. 1SY02-3
Innate immunity in atherosclerosis
The long pentraxin PTX3: From innate immunity to ischemic heart disorders
Inflammatory activators in the acute coronary syndromes
P. Libby. Brigham and Women’s Hospital, USA Recently a combination of clinical and laboratory observations have transformed our understanding of the mechanisms underlying the acute coronary syndromes. Thrombosis on the substrate of a disrupted atheromatous plaque rather than a critical fixed stenosis causes most acute coronary events. The physical integrity of the plaque, notably of the extracellular matrix of the fibrous capsule overlying the atheroma’s thrombogenic lipid core, thus governs the most important clinical manifestations of atherosclerosis. Atheromata that have ruptured and caused fatal acute myocardial infarction usually have thin fibrous caps, and large lipid pools. Accumulating evidence implicates inflammation as a critical determinant of the stability of human atherosclerotic plaques. Plaques that rupture generally have more abundant leukocytic infiltrates than those considered stable. Patients with signs of inflammation measured in the peripheral blood have increased risk of future coronary events. Inflammatory mediators such as cytokines can influence several biological processes that regulate stability of the plaque’s fibrous cap, hence its resistance to rupture. Inflammatory cytokines such as interleukin-1, tumor necrosis factor (TNF), and the cell surface homologue of TNF-α known as CD-40 ligand can also elicit the expression by macrophages and smooth muscle cells of enzymes that can weaken the extracellular matrix. The role of inflammation in the biology of the acute coronary syndromes has clinical as well as pathophysiologic relevance. First, circulating levels of soluble forms of certain cytokines, particularly CD40 ligand, as well as downstream inflammatory markers such as C-reactive protein can predict prognosis of patients with acute coronary syndromes. Second, modulators of inflammation may have a role in the prevention and treatment of the thrombotic complications of atherosclerosis.
L. Curtiss. The Scripps Research Institute, Department of Immunology, La Jolla, CA, USA Atherosclerosis involves a chronically inflamed state of the vessel wall. In lesions, many indicators of inflammation are present including soluble inflammatory mediators such as cytokines and chemokines, inflammatory cells such as macrophages, and endothelial cells covering the lesion expressing an inflamed phenotype. Toll-like receptors (TLRs) are at the heart of inflammation initiated by the innate immune system. The TLRs and especially TLRs 2 and 4 are essential for detecting the presence of microbial pathogens. In the absence of TLR2 or TLR4, an effective innate immune response to infection does not develop in time to curb microbial growth and the host dies of bacteremia. In atherosclerosis, roles for TLRs are unknown. We took advantage of bone marrow transplant (BMT) technology to test the hypothesis that ablation of TLR4 or TLR2 responses in bone marrow-derived cells (BMDC) would alter lesion progression. BMT of cells from TLR2-/-, TLR4-/-, or MYD88-/- mice into lethally irradiated LDLR-/- mice yielded three sets of chimeric mice. After a 4-week period of recovery from the BMT procedure, the mice were fed a high fat diet (HFD) to induce rapid atherosclerotic lesion development. Mouse weights and plasma cholesterol levels were monitored after BMT. At 12 weeks post-BMT, the mice were sacrificed and lesion areas in their aortas and at the aortic sinus were assessed. The data indicate that TLR2-/- BMDC made no difference to the progression of atherosclerosis in the LDLR-/- mice. However, TLR4-/- or MyD88-/- BMDC permitted accelerated atherosclerotic lesion development inasmuch as these mice had significantly increased lesion areas. The data for TLR4 and MyD88 suggest that expression of these molecules in the BMDC is atheroprotective and suggest that a certain low level of TLR4 activation, perhaps initiated by endogenous agonists, leads to a beneficial lesion repair process. XIIIth International Symposium on Atherosclerosis, September 28–October 2, 2003, Kyoto, Japan