title: 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.
authors.affiliation: Mucosal Inflammation Program, Department of Anesthesiology, University of Colorado Denver, Aurora, Colorado, United States of America.
authors.forename: Heidi
authors.initials: H
authors.lastname: Ehrentraut
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Westrich
authors.forename: Holger K
authors.initials: HK
authors.lastname: Eltzschig
authors.forename: Eric T
authors.initials: ET
authors.lastname: Clambey
mesh_terms: D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004731:Endotoxins / Q000633:toxicity*; D005434:Flow Cytometry; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D011014:Pneumonia / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D043704:Receptor, Adenosine A2B / Q000235:genetics / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*
chemical_list: D004731:Endotoxins; D043704:Receptor, Adenosine A2B; D019830:Adenosine-5'-(N-ethylcarboxamide)