The A2B adenosine receptor protects against inflammation and excessive vascular adhesion.
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-alpha, and a consequent downregulation of IkappaB-alpha 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.
Yang
Dan
D
Department of Biochemistry and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Zhang
Ying
Y
Nguyen
Hao G
HG
Koupenova
Milka
M
Chauhan
Anil K
AK
Makitalo
Maria
M
Jones
Matthew R
MR
St Hilaire
Cynthia
C
Seldin
David C
DC
Toselli
Paul
P
Lamperti
Edward
E
Schreiber
Barbara M
BM
Gavras
Haralambos
H
Wagner
Denisa D
DD
Ravid
Katya
K
D000818:Animals; D001808:Blood Vessels / Q000166:cytology / Q000502:physiology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D016026:Bone Marrow Transplantation; D002448:Cell Adhesion / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism; D019040:E-Selectin / Q000378:metabolism; D005260:Female; D017930:Genes, Reporter; D007249:Inflammation / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D036904:Leukocyte Rolling; D051379:Mice; D018345:Mice, Knockout; D019007:P-Selectin / Q000378:metabolism; D043704:Receptor, Adenosine A2B / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D016207:Cytokines; D019040:E-Selectin; D019007:P-Selectin; D043704:Receptor, Adenosine A2B; D018799:Intercellular Adhesion Molecule-1