Extracellular ATP and adenosine have immunoregulatory roles during inflammation. Elevated extracellular ATP is known to exacerbate GVHD, and the pharmacologic activation of the adenosine A2A receptor is protective. However, the role of endogenous adenosine is unknown. We used gene-targeted mice and a pharmacologic inhibitor to test the role of adenosine generated by CD73/ecto-5'-nucleotidase in GVHD. In allogeneic transplants, both donor and recipient CD73 were protective, with recipient CD73 playing the dominant role. CD73 deficiency led to enhanced T-cell expansion and IFN-γ and IL-6 production, and the migratory capacity of Cd73-/- T cells in vitro was increased. However, the number of regulatory T cells and expression of costimulatory molecules on antigen-presenting cells were unchanged. A2A receptor deficiency led to increased numbers of allogeneic T cells, suggesting that signaling through the A2A receptor via CD73-generated adenosine is a significant part of the mechanism by which CD73 limits the severity of GVHD. Pharmacologic blockade of CD73 also enhanced graft-versus-tumor activity. These data have clinical implications, as both the severity of GVHD and the strength of an alloimmune antitumor response could be manipulated by enhancing or blocking CD73 activity or adenosine receptor signaling depending on the clinical indication.
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http://dx.doi.org/10.1182/blood-2011-09-375899 | DOI Listing |
J Neurochem
January 2025
FMUC-Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
Astrocytes participate in brain clearance of extracellular proteins and metabolites, through the activity of the water channel aquaporin-4 (AQP4), which can be deregulated in stress-related disorders, impairing brain waste clearance. The present study investigates the impact of dexamethasone (Dexa), a synthetic glucocorticoid used as a simplified in vitro stress model, on astrocytic AQP4 and its modulation by adenosine A receptors (AR), which blockade reverses conditions related with maladaptive stress, such as anxiety and depression. The clearance of proteins in primary astrocytic cultures, assessed using 5 kDa FITC-dextran and 45 kDa TRITC-dextran uptake, was decreased by a 24 h exposure to 100 nM Dexa.
View Article and Find Full Text PDFFront Pharmacol
December 2024
Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
Introduction: The paraventricular thalamic nucleus (PVT) is recognized for its critical role in pain regulation, yet the precise molecular mechanisms involved remain poorly understood. Here, we demonstrated an essential role of the microglial adenosine A receptor (AR) in the PVT in regulating pain sensation and non-opioid analgesia.
Method And Results: Specifically, AR was predominantly expressed in ionized calcium binding adapter molecule 1 (Iba1)-positive microglia cells within the PVT, with expression levels remaining unchanged in mice experiencing persistent inflammatory pain induced by complete Freund's adjuvant (CFA).
Nat Commun
December 2024
PSI Center for Life Sciences, Villigen PSI, Switzerland.
G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors in humans. The binding and dissociation of ligands tunes the inherent conformational flexibility of these important drug targets towards distinct functional states. Here we show how to trigger and resolve protein-ligand interaction dynamics within the human adenosine A receptor.
View Article and Find Full Text PDFNeuropharmacology
December 2024
College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, Republic of Korea. Electronic address:
Neuroinflammation plays a crucial role in the pathogenesis of Parkinson's disease (PD). Transformation of pro-interleukin (IL)-1β into a mature IL-1β via active inflammasome may be related to the progression of PD. Therefore, the modification of inflammasome activity may be a potential therapeutic strategy for PD.
View Article and Find Full Text PDFBiomed Rep
February 2025
Institute of Sports Medicine and Health, Chengdu Sport University, Chengdu, Sichuan 641418, P.R. China.
Obstructive sleep apnea (OSA) is the most common type of sleep apnea, which leads to episodes of intermittent hypoxia due to obstruction of the upper airway. A key feature of OSA is the upregulation and stabilization of hypoxia-inducible factor 1 (HIF-1), a crucial metabolic regulator that facilitates rapid adaptation to changes in oxygen availability. Adenosine A2A receptor (A2AR), a major adenosine receptor, regulates HIF-1 under hypoxic conditions, exerting anti-inflammatory properties and affecting lipid metabolism.
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