Losartan attenuates human monocyte-derived dendritic cell immune maturation via downregulation of lectin-like oxidized low-density lipoprotein receptor-1.
ABSTRACT The angiotensin II receptor-1 blockers have generally been shown to have antiatherogenic effects, and dendritic cells (DCs) are the most efficient antigen presenting cells that play an active role in the development of atherosclerosis through inflammatory-immune responses. Here, we tested the hypothesis that the antiatherogenic effect of losartan, the first angiotensin II receptor-1 blockers, might partly be mediated by attenuating DCs maturation. In this study, we showed that oxidized low-density lipoprotein (oxLDL) and angiotensin II (Ang II) could induce the maturation of human monocyte-derived DCs, stimulate CD83, HLA-DR expressions and IL-12, interferon-gamma secretions and increase the capacity of DCs to stimulate T-cell proliferation, which were suppressed by losartan. OxLDL could promote the autocrine secretion of Ang II by DCs and upregulate the expressions of 3 scavenger receptors SR-A, CD36, and LOX-1. Losartan reduced oxLDL-induced LOX-1 expression but not SR-A and CD36 expressions. Ang II could only upregulate the LOX-1 expression, which was reduced by losartan. OxLDL- and Ang II-induced upregulation of CD83 and secretion of IL-12 were all attenuated by LOX-1 neutralizing antibody. In conclusion, losartan could attenuate the oxLDL- and Ang II-induced immune maturation of human monocyte-derived DCs partly through downregulation of the LOX-1 expression.
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ABSTRACT: Angiotensin (Ang) II promotes renal infiltration by immunocompetent cells in double-transgenic rats (dTGRs) harboring both human renin and angiotensinogen genes. To elucidate disease mechanisms, we investigated whether or not dexamethasone (DEXA) immunosuppression ameliorates renal damage. Untreated dTGRs developed hypertension, renal damage, and 50% mortality at 7 weeks. DEXA reduced albuminuria, renal fibrosis, vascular reactive oxygen stress, and prevented mortality, independent of blood pressure. In dTGR kidneys, p22phox immunostaining co-localized with macrophages and partially with T cells. dTGR dendritic cells expressed major histocompatibility complex II and CD86, indicating maturation. DEXA suppressed major histocompatibility complex II+, CD86+, dendritic, and T-cell infiltration. In additional experiments, we treated dTGRs with mycophenolate mofetil to inhibit T- and B-cell proliferation. Reno-protective actions of mycophenolate mofetil and its effect on dendritic and T cells were similar to those obtained with DEXA. We next investigated whether or not Ang II directly promotes dendritic cell maturation in vitro. Ang II did not alter CD80, CD83, and MHC II expression, but increased CCR7 expression and cell migration. To explore the role of tumor necrosis factor (TNF)-alpha on dendritic cell maturation in vivo, we treated dTGRs with the soluble TNF-alpha receptor etanercept. This treatment had no effect on blood pressure, but decreased albuminuria, nuclear factor-kappaB activation, and infiltration of all immunocompetent cells. These data suggest that immunosuppression prevents dendritic cell maturation and T-cell infiltration in a nonimmune model of Ang II-induced renal damage. Ang II induces dendritic migration directly, whereas in vivo TNF-alpha is involved in dendritic cell infiltration and maturation. Thus, Ang II may initiate events leading to innate and acquired immune response.American Journal Of Pathology 12/2002; 161(5):1679-93. · 4.52 Impact Factor
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ABSTRACT: Dendritic cells (DCs) accumulate in atherosclerotic lesions but their characteristics and their role in atherogenesis are poorly understood. C1q, an element of the first component of complement, is expressed by interdigitating dendritic cells and follicular dendritic cells in the spleen. It has been suggested that C1q is involved in capturing immune complexes in the lymphoid tissue. Immune complexes are also detected in atherosclerotic lesions. The present study investigated whether C1q is expressed by DCs in the arterial wall. Because DCs accumulating within atherosclerotic lesions might originate from monocytes that infiltrate the intima from very early stages of atherosclerosis, C1q expression was also examined in monocyte-derived DCs in vitro. Specimens of the aorta, carotid, mammary, popliteal and tibial arteries were obtained during operation. Expression of C1q in the arterial wall was studied by immunohistochemistry. The nature of cells expressing C1q was studied in sections double stained with antibodies to C1q and cell type specific markers including CD1a and S-100 (for identification of DCs), CD68 (macrophages), CD3 (T-cells), von Willebrand factor (endothelial cells), and smooth muscle alpha-actin (smooth muscle cells). In vitro, DCs were differentiated from human peripheral blood monocytes using GM-CSF and IL-4. Peripheral blood monocytes were differentiated to macrophages using M-CSF. The expression of C1q in monocytes and in vitro monocyte-derived DCs and macrophages was determined by RT-PCR, Western blotting, immunofluorescence microscopy and flow cytometry. In all the arterial specimens studied, DCs expressing C1q were detected. C1q was also found in macrophages, macrophage foam cells and in neovascular endothelial cells in atherosclerotic lesions, but no C1q expression was detected in T-cells and smooth muscle cells. In vitro analysis demonstrated that monocyte-derived DCs and macrophages express C1q but no C1q was detected in monocytes. C1q is expressed by DCs residing in the arterial wall as well as by monocyte-derived DCs in vitro. Expression of C1q occurs during differentiation of monocytes to DCs and macrophages and might be important in binding and trapping immune complexes in atherosclerotic lesions.Cardiovascular Research 11/2003; 60(1):175-86. · 5.94 Impact Factor
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ABSTRACT: Both advanced glycosylation end products (AGEs) and dendritic cells (DCs) have been shown to play a causative role in atherosclerosis. However, whether they function interactively in the process remains uncertain. We therefore studied the effects of AGE-bovine serum albumin (AGE-BSA) on the maturation of DCs and the expressions of scavenger receptor-A (SR-A) and receptor for AGEs (RAGE) on DCs. AGE-BSA induced DCs maturation accompanied with increased expressions of CD1a, CD40, CD80, CD83, CD86, and MHC class II. The capacity of DCs to stimulate T-cell proliferation and secretion of cytokines (interferon [IFN], IFN-gamma, interleukin [IL]-10 and IL-12) was also enhanced by AGE-BSA. AGE-BSA significantly upregulated SR-A and RAGE expression on DCs and the upregulation was abolished by inhibition of mitogen-activated protein (MAP) kinase Jnk, but not by that of Erk and p38 MAP kinase. AGE-BSA-induced expression of CD83 and secretion of IL-12 were partly inhibited by either an anti-RAGE neutralizing antibody or a Jnk inhibitor. AGE-BSA induces maturation of DCs and augmented their capacity to stimulate T-cell proliferation and cytokine secretions possibly through upregulation of RAGE and SR-A, which at least in part through Jnk. These findings might explain in part the interactive roles of AGEs and DCs in the processes of atherosclerosis.Arteriosclerosis Thrombosis and Vascular Biology 11/2005; 25(10):2157-63. · 6.34 Impact Factor