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Objective-Based on the emerging importance of the wingless (Wnt) pathways in inflammation and vascular biology, we hypothesized a role for Dickkopf-1 (DKK-1), a major modulator of Wnt signaling, in atherogenesis and plaque destabilization. Methods and Results-We report increased levels of DKK-1 in experimental (ApoE Ϫ/Ϫ mice) and clinical (patients with coronary artery disease ͓nϭ80͔ and patients with carotid plaque ͓nϭ47͔) atherosclerosis, both systemically (serum) and within the lesion, with particularly high levels in advanced and unstable disease. We identified platelets as an important cellular source of DKK-1 as shown by in vitro experiments and by immunostaining of thrombus material obtained at the site of plaque rupture in patients with acute ST-elevation myocardial infarction, with strong immunoreactivity in platelet aggregates. Our in vitro experiments identified a role for platelet-and endothelialderived DKK-1 in platelet-dependent endothelial activation, promoting enhanced release of inflammatory cytokines. These inflammatory effects of DKK-1 involved inhibition of the Wnt/␤-catenin pathway and activation of nuclear factor B. Key Words: atherosclerosis Ⅲ endothelium Ⅲ inflammation Ⅲ platelets P roteins from the wingless (Wnt) signaling pathways are involved in diverse developmental and physiological processes, including cardiac and vascular development. Wnt signals are transduced to the canonical and the noncanonical pathways for control of cell fate, cell movement, and tissue polarity. 1 The Wnt pathways are regulated by multiple families of secreted antagonists including soluble frizzled related receptors and dickkopfs (DKK). The best studied of these is DKK-1, which dampens Wnt signaling by binding to the low-density lipoprotein receptor-related protein (LRP)5/6 and a cell surface coreceptor, Kremen-1, promoting internalization of the receptor complex. 2 In adults, DKK-1 has been implicated in bone disease, cancer, and brain ischemia, and most recently, the destructive effect of tumor necrosis factor ␣ (TNF␣) on joints in rheumatoid arthritis was found to involve DKK-1. 2,3 Also, serum levels of DKK-1 give prognostic information in patients with multiple myeloma and other malignancies as well as in patients with osteoarthritis. 4,5 Recent evidence points to an important role of the Wnt signaling pathways in the regulation of inflammation. Thus, activation of the canonical Wnt/␤-catenin pathway induces proliferation and survival of endothelial cells, enhances monocyte adhesion, and regulates transendothelial migration of monocytes. 6 -9 Moreover, activation of the noncanonical pathway has been shown to regulate inflammatory responses of human monocytes and macrophages in vitro. 10,11 However, the interaction between the different proteins in the Wnt family is rather complex, and the role Conclusion-Our

Objective-Based on its role in inflammation and matrix degradation, we hypothesized a role for osteoprotegerin (OPG), RANK, and RANK ligand (RANKL) in coronary artery disease. Methods and Results-We examined the expression of various members of the OPG/RANKL/RANK axis in patients with stable and unstable angina and in the atherosclerotic lesions of apolipoprotein E-deficient (apoE Ϫ/Ϫ ) mice. Our findings were: (1) Serum levels of OPG were raised in patients with unstable angina (nϭ40), but not in those with stable angina (nϭ40), comparing controls (nϭ20); (2) mRNA levels of RANKL were increased in T-cells in unstable angina patients accompanied by increased expression of RANK in monocytes; (3) strong immunostaining of OPG/RANKL/RANK was seen within thrombus material obtained at the site of plaque rupture during acute myocardial infarction; (4) OPG/RANKL/RANK was expressed in the atherosclerotic plaques of apoE Ϫ/Ϫ mice, with RANKL located specifically to the plaques; and (5) Key Words: arteriosclerosis Ⅲ inflammation Ⅲ plaque stability N umerous inflammatory mediators seem to play a pathogenic role in coronary artery disease (CAD), promoting atherogenesis and plaque destabilization, leading to thrombus formation with development of acute coronary syndromes. 1,2 However, although the participation of inflammatory mediators in the atherosclerotic process has become widely recognized, the identification and characterization of the different actors are not fulfilled.Receptor activator of nuclear factor-kB ligand (RANKL), its membrane-bound receptor RANK and its soluble decoy receptor osteoprotegerin (OPG) are members of the tumor necrosis factor (TNF) receptor superfamily. These factors have been identified as candidate mediators for paracrine signaling in bone metabolism but are also involved in modulation of the immune response through interaction with dendritic cells, T-cell activation, and B-cell maturation. 3,4 The pleiotropic effects of the OPG/RANKL/RANK system, such as modulation of cell survival, mineralization and inflammation, make it an interesting candidate mediator in the progression and destabilization of atherosclerotic lesions. mRNA and protein expression of OPG and RANKL have been detected in atherosclerotic plaques in humans. 5,6 Moreover, raised serum levels of OPG are reported in CAD patients and have also been shown to predict cardiovascular mortality in elderly women. 7-9 Although these findings may suggest the involvement of the OPG/RANKL/RANK system in atherogenesis, our knowledge of the role of this system in human CAD, and particularly in acute coronary syndromes, is still limited.Based on its involvement in inflammation and matrix degradation, we in the present study attempted to further clarify the potential role of the OPG/RANKL/RANK system in atherogenesis and acute coronary syndromes by different approaches including clinical studies in patients with sta-

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The abnormal regulation of CCL19 and CCL21 and their common receptor in atherosclerosis could contribute to disease progression by recruiting T-cells and macrophages to the atherosclerotic lesions and by promoting inflammatory responses in these cells.

BackgroundRespirable crystalline silica (silicon dioxide; SiO2, quartz) particles are known to induce chronic inflammation and lung disease upon long-term inhalation, whereas non-crystalline (amorphous) SiO2 particles in the submicrometre range are regarded as less harmful. Several reports have demonstrated that crystalline, but also non-crystalline silica particles induce IL-1β release from macrophages via the NALP3-inflammasome complex (caspase-1, ASC and NALP3) in the presence of lipopolysaccharide (LPS) from bacteria. Our aim was to study the potential of different non-crystalline SiO2 particles from the nano- to submicro-sized range to activate IL-1β responses in LPS-primed RAW264.7 macrophages and primary rat lung macrophages. The role of the NALP3-inflammasome and up-stream mechanisms was further explored in RAW264.7 cells.ResultsIn the present study, we have shown that 6 h exposure to non-crystalline SiO2 particles in nano- (SiNPs, 5–20 nm, 50 nm) and submicro-sizes induced strong IL-1β responses in LPS-primed mouse macrophages (RAW264.7) and primary rat lung macrophages. The primary lung macrophages were more sensitive to Si-exposure than the RAW-macrophages, and responded more strongly. In the lung macrophages, crystalline silica (MinUsil 5) induced IL-1β release more potently than the non-crystalline Si50 and Si500, when adjusted to surface area. This difference was much less pronounced versus fumed SiNPs. The caspase-1 inhibitor zYVAD and RNA silencing of the NALP3 receptor reduced the particle-induced IL-1β release in the RAW264.7 macrophages. Furthermore, inhibitors of phagocytosis, endosomal acidification, and cathepsin B activity reduced the IL-1β responses to the different particles to a similar extent.ConclusionsIn conclusion, non-crystalline silica particles in the nano- and submicro-size ranges seemed to induce IL-1β release from LPS-primed RAW264.7 macrophages via similar mechanisms as crystalline silica, involving particle uptake, phagosomal leakage and activation of the NALP3 inflammasome. Notably, rat primary lung macrophages were more sensitive with respect to silica-induced IL-1β release. The differential response patterns obtained suggest that silica-induced IL-1β responses not only depend on the particle surface area, but on factors and/or mechanisms such as particle reactivity or particle uptake. These findings may suggest that bacterial infection via LPS may augment acute inflammatory effects of non-crystalline as well as crystalline silica particles.

Objective-Recent data derived primarily from studies in animal models suggest that fractalkine (CX3CL1) and its cognate receptor, CX3CR1, play a role in atherogenesis. We, therefore, hypothesized that enhanced CX3CL1/CX3CR1 expression may promote atherogenesis in patients with coronary artery disease (CAD). Methods and Results-We examined the plasma levels of CX3CL1 and CX3CR1 expression in peripheral blood mononuclear cells (PBMC) in various CAD populations (30 patients with previous myocardial infarction, 40 patients with stable angina, 40 patients with unstable angina, and a total of 35 controls) and used various experimental approaches to characterize CX3CL1-mediated leukocyte responses. We found that the plasma levels of CX3CL1 are greatly increased in CAD, particularly in unstable disease. The parallel increase of CX3CR1 expression in PBMC was predominantly attributable to an expansion of the CX3CR1 ϩ CD3 ϩ CD8 ϩ T cell subset and was associated with enhanced chemotactic, adhesive, and inflammatory responses to CX3CL1. Statin therapy for 6 months reduced the expression of CX3CL1 and CX3CR1, reaching statistical significance for both parameters only during aggressive (atorvastatin, 80 mg qd) but not conventional (simvastatin, 20 mg qd) therapy. Consequently, the functional responses of the PBMC to CX3CL1 including migration, adhesion, and secretion of interleukin-8 were attenuated by the treatments. Key Words: atherosclerosis Ⅲ coronary artery disease Ⅲ cytokines Ⅲ immune system Ⅲ leukocytes B esides lipid deposition and vascular smooth muscle cell (VSMC) proliferation, the infiltration of monocytes and T cells is a cardinal feature of atherosclerotic plaques of all stages. 1,2 This persistent recruitment of mononuclear cells into the vessel wall is a critical step in atherogenesis, and growing evidence suggests that chemokines are involved in these processes by activating and directing leukocytes into atherosclerotic lesions. 3,4 Fractalkine (CX3CL1) is the unique member of the CX3C chemokine subfamily. In contrast to other chemokines, it exists in two forms, each mediating distinct biological actions. 5 The membrane-anchored protein, which is expressed primarily on the inflamed endothelium, serves as an adhesion protein promoting the retention of monocytes and T cells. 6 The soluble form resembles more a conventional chemokine and strongly induces chemotaxis. Both chemotaxis and adhesion are mediated by the G protein-coupled receptor CX3CR1. 7,8 Based on these chemotactic and adhesive properties, CX3CL1 has been suggested to play an important role in inflammation and accumulating evidence indicates that CX3CL1/CX3CR1 are involved in the pathogenesis of various inflammatory disorders. 9,10 Recently, two independent reports showed that the targeted deletion of CX3CR1 decreased atherosclerosis in mice, implicating a role of this chemokine system in atherogenesis. 11,12 Moreover, Lucas et al and Greaves et al have recently shown expression of CX3CL1 and CX3CR1 in human coronary atherosclerotic plaques, 13,14 ...

Summary Common variable immunodeficiency (CVID) is