Adora2b Adenosine Receptor Engagement Enhances Regulatory T Cell Abundance during Endotoxin-Induced Pulmonary Inflammation

Abstract

Anti-inflammatory signals play an essential role in constraining the magnitude of an inflammatory response. Extracellular adenosine is a critical tissue-protective factor, limiting the extent of inflammation. Given the potent anti-inflammatory effects of extracellular adenosine, we sought to investigate how extracellular adenosine regulates T cell activation and differentiation. Adenosine receptor activation by a pan adenosine-receptor agonist enhanced the abundance of murine regulatory T cells (Tregs), a cell type critical in constraining inflammation. Gene expression studies in both naïve CD4 T cells and Tregs revealed that these cells expressed multiple adenosine receptors. Based on recent studies implicating the Adora2b in endogenous anti-inflammatory responses during acute inflammation, we used a pharmacologic approach to specifically activate Adora2b. Indeed, these studies revealed robust enhancement of Treg differentiation in wild-type mice, but not in Adora2b −/− T cells. Finally, when we subjected Adora2b-deficient mice to endotoxin-induced pulmonary inflammation, we found that these mice experienced more severe inflammation, characterized by increased cell recruitment and increased fluid leakage into the airways. Notably, Adora2b-deficient mice failed to induce Tregs after endotoxin-induced inflammation and instead had an enhanced recruitment of pro-inflammatory effector T cells. In total, these data indicate that the Adora2b adenosine receptor serves a potent anti-inflammatory role, functioning at least in part through the enhancement of Tregs, to limit inflammation.

Adenosine Modulates NR4A Orphan Nuclear Receptors To Attenuate Hyperinflammatory Responses in Monocytic Cells

“…Interestingly, adenosine has been shown to promote Treg development and inhibit proinflammatory Th17 responses through A2a receptor signaling (49,50). More recent studies endorse the observation that adenosine-dependent Treg recruitment, via A2bR engagement, helps to limit inflammatory responses in endotoxininduced pulmonary inflammation (51). Notably, under physiological and pathological conditions, NR4A2 controls Treg induction and suppression of aberrant production of Th1 cytokines (17,18).…”

CD73-Dependent Generation of Adenosine and Endothelial Adora2b Signaling Attenuate Diabetic Nephropathy

“…65 Similarly, Adora2b signaling has been implicated in promoting regulatory T cells and inflammation resolution. 66 Because T cell activation plays an important role in the pathophysiology of diabetic organ injury, 67 future studies toward a possible role of adenosine in regulating T-cell activation could be of great clinical relevance. Taken together, the present studies implicate the CD73-dependent generation of extracellular adenosine and signaling through endothelial-expressed Adora2b receptors in kidney protection during diabetic nephropathy.…”

Concurrent Agonism of Adenosine A2Band Glucocorticoid Receptors in Human Airway Epithelial Cells Cooperatively Induces Genes with Anti-Inflammatory Potential: A Novel Approach to Treat Chronic Obstructive Pulmonary Disease

“…The scientific rationale for this idea is based on two important assumptions: 1) Bay 60-6583 and dexamethasone induce distinct subpopulations of antiinflammatory genes, and 2) Bay 60-6583 and dexamethasone when used in combination target a different but common population of anti-inflammatory genes that are up-regulated in an additive or positive cooperative manner. Of the four known adenosine receptors, the A 2B -subtype was identified as a possible target for several reasons (Blackburn et al, 2009;Aherne et al, 2011;Ehrentraut et al, 2012). First, it is expressed ubiquitously across human proinflammatory and immune cells.…”