Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Interleukin-7 promotes monocyte/macrophage arrest on endothelial cells

ABSTRACT: Background: It is recognized that atherosclerosis can regresses at least in animal models. However, little is known about the mechanisms. We induced regression of advanced atherosclerosis in apolipoprotein E deficient (APOE/) mice and studied underlying mechanisms. Unexpectedly, our study led to the role of interleukin-7 (IL-7) in atherogenesis. Methods and Results: We treated APOE/ mice fed a high cholesterol diet for 30 weeks to induce advanced lesions with a helper-dependent adenoviral vector expressing human apoE3 (HDAd-gE3), and analyzed the regression of atherosclerosis after 41 weeks. Using microarray analysis, we identified IL-7 as one of most significantly affected genes by lowering cholesterol. To answer why IL-7 is downregulated by reduced cholesterol, we studied effects of IL-7 on endothelial cells (ECs). Our major findings were (1) long-term lowering cholesterol induced regression of advanced atherosclerosis. (2) Microarray analysis identified multiple signaling pathways affected by lowering cholesterol. (3) Correction for multiple testing revealed that IL-7 expression was downregulated, whereas gamma-sarcoglycan and Î±-actin were upregulated. (4) Oxidized LDL upregulated IL-7 expression in macrophages but not in aorta ECs or smooth muscle cells. (5) IL-7 increased the expression of cell adhesion molecules and chemokine in ECs and promoted monocyte adhesion to ECs. (6) Systemic elevation of IL-7 induced inflammatory response and recruited monocyte/macrophage to the lesions without increasing plasma cholesterol. Conclusion: Our finding suggest that IL-7 inflames endothelium and triggers the adhesion/recruitment of monocyte/macrophages to the atherosclerotic lesions and thus plays a direct role in development of atherosclerosis. Key Words: arteriosclerosis, gene therapy, hypercholesterolemia, interleukins, cell adhesion molecules Female APOE-/- mice (8 weeks of age) on a C57BL/6 background were purchased from Jackson Laboratory and were fed a diet containing 0.2% (w/w) cholesterol and 10% (v/w) coconut oil to induce atherosclerosis for 30 weeks. Mice were then divided into 3 groups, (n=15/group), treated with a tail vein injection of helper-dependent adenovirus expressing human apolipoprotein E3 (HDAd-gE3, 5 x 1012 viral particles/kg, n=11, vector), empty vector (HDAd-0, 5 x 1012 VP/kg, n=11, vector control) or phosphate buffered saline (PBS, vehicle) and sacrificed 10 days after. Three aortas extending sinus to arch were pooled for RNA extraction with an RNeasy kit (Qiagen). Sample ID 12031: E4: vector control (HDAd-0) 12043: E5: vector control 12046: V2: vector 12047: V3: vector 12048: V4: vector 12051: B1: vehicle (PBS) 12053: B3: vehicle 12054: B4: vehicle 12039: E3: vector control

ORGANISM(S): Mus musculus

SUBMITTER: Kazuhiro Oka

PROVIDER: E-GEOD-15914 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Interleukin-7 induces recruitment of monocytes/macrophages to endothelium.

Li Rongying R Paul Antoni A Ko Kerry W S KW Sheldon Michael M Rich Benjamin E BE Terashima Tomoya T Dieker Carrie C Cormier Shelley S Li Lan L Nour Elie A EA Chan Lawrence L Oka Kazuhiro K

European heart journal 20110730 24

<h4>Aims</h4>Interleukin-7 (IL-7) is a master regulator of T-cell development and homoeostasis. Increased IL-7 levels are associated with inflammatory diseases. The aims of this study were to determine whether IL-7 is a biomarker for inflammatory conditions or an active participant in atherogenesis.<h4>Methods and results</h4>Advanced atherosclerotic lesions in Apoe(-/-) mice were regressed by long-term cholesterol lowering through treatment with a helper-dependent adenovirus expressing apolipop ...[more]

PMID: 21804111

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Project description:Regression of atherosclerosis is an important clinical goal, however the pathways that mediate the resolution of atherosclerotic inflammation and reversal of plaques are poorly understood. Regulatory T cells (Tregs) have been shown to be atheroprotective, however numbers of these immunosuppressive cells decrease with disease progression. Using multiple independent mouse models of atherosclerosis regression, we demonstrate that an increase in plaque Tregs is a common signature of regressing plaques. To test if Tregs are required for the resolution of atherosclerotic inflammation and plaque regression during lipid-lowering therapy, we combined CD25 monoclonal antibody (PC61 mAb)-mediated Treg depletion with single-cell RNA-sequencing of immune cells in the plaque and conventional analyses of atherosclerosis. Single cell RNA-sequencing revealed that Tregs from aortic plaques shared some similarity with splenic Tregs, but were distinct from skin and colon Tregs supporting recent findings of tissue-dependent Treg heterogeneity. Furthermore, Tregs from progressing plaques expressed markers of natural Tregs derived from the thymus, whereas Tregs in regressing plaques lacked Nrp1 and Helios expression, suggesting that they are induced in the periphery during lipid lowering. Treatment of atherosclerotic mice with PC61 mAb effectively depleted Tregs in the blood and peripheral tissues, including plaques, and blocked the regression of atherosclerosis induced by apoB anti-sense oligonucleotides. Morphometric analyses revealed that control antibody-treated mice showed a 40% decrease in plaque burden and macrophage content under regression conditions, whereas PC61 mAb-treated mice showed no change in plaque size or inflammatory cell content compared to baseline. Moreover, Treg depletion enhanced inflammatory signaling and blocked tissue reparative functions of macrophages in the regressing plaque, including M2-polarization, efferocytosis and sensing of specialized pro-resolving lipid mediators. Together, these data establish essential roles for Tregs in the resolution of atherosclerotic inflammation and plaque remodeling during regression.

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Interleukin-7 promotes monocyte/macrophage arrest on endothelial cells

Publications

Interleukin-7 induces recruitment of monocytes/macrophages to endothelium.

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