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New insights into the regulation of inflammation by adenosine
Joel Linden
Department of Medicine and Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia, USA.
Address correspondence to: Joel Linden, Department of Medicine and the Cardiovascular Research Center, MR5 Box 801394, University of Virginia, Charlottesville, Virginia 22908, USA. Phone: (434) 924-5600; Fax: (434) 924-2828; E-mail: jlinden@virginia.edu .
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Published July 3, 2006 - More info
J Clin Invest. 2006;116(7):1835–1837. https://doi.org/10.1172/JCI29125.
© 2006 The American Society for Clinical Investigation
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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
There is growing interest in elucidating the mechanisms by which adenosine inhibits the immune system, since these inhibitory adenosine receptors and their downstream signaling pathways are promising targets for new antiinflammatory therapies. By signaling through the A2A adenosine receptor (A2AAR), adenosine suppresses the immune system, primarily by inhibiting lymphoid or myeloid cells including neutrophils (1), macrophages (2), lymphocytes (3, 4), and platelets (5). These responses are amplified by rapid induction of A2AAR mRNA in macrophages and T lymphocytes in response to inflammatory or ischemic stimuli (2, 3, 6, 7). The A2B adenosine receptor (A2BAR) also appears to mediate antiinflammatory effects in macrophages by inhibiting the production of TNF-α and IL-1β, stimulating IL-10 and inhibiting macrophage proliferation (8–11) (Figure 1A). Macrophage A2BAR signaling increases during inflammation, as the macrophage-activating cytokine IFN-γ causes induction of macrophage A2BAR mRNA (12). However, the A2BAR is somewhat unusual in that it is dually coupled to the generally antiinflammatory G protein Gs and the generally proinflammatory G protein Gq (13); in addition, numerous proinflammatory effects mediated by activation of the A2BAR have also been described (Table 1).
Figure 1Anti- and proinflammatory effects mediated by activation of the A2B AR. (A) In macrophages, the release of TNF-α and other proinflammatory cytokines is inhibited as a result of activating either the A2AAR or the A2BAR. These effects are amplified if TNF-α production is stimulated by LPS, which signals through TLR4 and other Toll-like receptors. Activation of the A2BAR also stimulates production of the antiinflammatory cytokine IL-10. (B) In endothelial cells and other cells noted in Table 1, activation of the A2BAR stimulates IL-6 and other proinflammatory cytokines. Hypoxia increases the intracellular production of adenosine, which is transported outside the cell by nucleoside transport proteins. Hypoxia and possibly activation of the A2BAR stimulate the release of ATP and the production of the A2BAR and ectoenzymes (CD39 and CD73) that convert ATP to adenosine. Vasodilation in response to A2BAR activation may increase shear stress to stimulate ATP release.
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