The A2B adenosine receptor protects against inflammation and excessive vascular adhesion
Dan Yang, … , Denisa D. Wagner, Katya Ravid
Dan Yang, … , Denisa D. Wagner, Katya Ravid
Published July 3, 2006
Citation Information: J Clin Invest. 2006;116(7):1913-1923. https://doi.org/10.1172/JCI27933.
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Research Article Cardiology

The A2B adenosine receptor protects against inflammation and excessive vascular adhesion

Abstract

Adenosine has been described as playing a role in the control of inflammation, but it has not been certain which of its receptors mediate this effect. Here, we generated an A2B adenosine receptor–knockout/reporter gene–knock-in (A2BAR-knockout/reporter gene–knock-in) mouse model and showed receptor gene expression in the vasculature and macrophages, the ablation of which causes low-grade inflammation compared with age-, sex-, and strain-matched control mice. Augmentation of proinflammatory cytokines, such as TNF-α, and a consequent downregulation of IκB-α are the underlying mechanisms for an observed upregulation of adhesion molecules in the vasculature of these A2BAR-null mice. Intriguingly, leukocyte adhesion to the vasculature is significantly increased in the A2BAR-knockout mice. Exposure to an endotoxin results in augmented proinflammatory cytokine levels in A2BAR-null mice compared with control mice. Bone marrow transplantations indicated that bone marrow (and to a lesser extent vascular) A2BARs regulate these processes. Hence, we identify the A2BAR as a new critical regulator of inflammation and vascular adhesion primarily via signals from hematopoietic cells to the vasculature, focusing attention on the receptor as a therapeutic target.

Authors

Dan Yang, Ying Zhang, Hao G. Nguyen, Milka Koupenova, Anil K. Chauhan, Maria Makitalo, Matthew R. Jones, Cynthia St. Hilaire, David C. Seldin, Paul Toselli, Edward Lamperti, Barbara M. Schreiber, Haralambos Gavras, Denisa D. Wagner, Katya Ravid

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Figure 2

β-Gal expression in different tissues.

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β-Gal expression in different tissues. (A) β-Gal staining of different o...
(A) β-Gal staining of different organs derived from WT or KO mice and captured at the indicated magnifications (in parenthesis on the left) with an Olympus IX70 microscope combined with a Hamamatsu charge-coupled device camera (C4742-95). (B) Histological examination of tissue sections derived from the organs shown in A. The arrows point to the VSMC layer. Fold magnifications of captured images are indicated above each column (×200 or ×600). (C) Electron microscopic examination of arteries. In order to ascertain β-gal expression in the endothelial layer and further confirm expression in smooth muscle cells, we applied electron microscopic examination. The red arrow indicates endothelial cells, the light blue arrow elastin, and the dark blue arrow the VSMC layer. Original magnification, ×6,400. The black stain is indicative of β-gal staining. As control, WT mice were subjected to similar staining, showing no expression. (D) β-Gal expression was evident in peritoneal macrophages isolated and processed as described in Methods. The isolation procedure yielded a preparation enriched with macrophages (to 35–40% of total cells).