{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T21:03:13Z","timestamp":1788210193242,"version":"build-2803163510"},"reference-count":110,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Axial Spondyloarthritis (AS) is a chronic immune-mediated disease of the axial skeleton characterized by persistent inflammation and pathological bone formation driven by reciprocal signaling between immune and stromal cells. Central to this interplay is adenosine\u2014a key metabolic regulator of immune tolerance and tissue remodeling. In AS, purinergic homeostasis is profoundly disrupted: the ectonucleotidases CD39 and CD73, responsible for adenosine synthesis, are downregulated, while adenosine-degrading enzymes ADA and its surface anchor CD26 are upregulated. This enzymatic disequilibrium depletes adenosine in inflamed tissues, impairs FOXP3\n                    <jats:sup>+<\/jats:sup>\n                    regulatory T cell induction, and amplifies Th17-driven inflammation and fibroblast activation. We propose a stage-specific therapeutic framework for restoring adenosine balance in AS encompassing: (1) reconstitution of CD39\/CD73 enzymatic activity, (2) receptor-selective modulation of A\n                    <jats:sub>2<\/jats:sub>\n                    A and A\n                    <jats:sub>2<\/jats:sub>\n                    B signaling pathways, and (3) exosome-mediated delivery of adenosine-regulating enzymes and microRNAs to reestablish immune homeostasis with cellular precision. The dual nature of adenosine\u2014anti-inflammatory through A\n                    <jats:sub>2<\/jats:sub>\n                    A receptor activation and pro-fibrotic via A\n                    <jats:sub>2<\/jats:sub>\n                    B receptor engagement\u2014necessitates context-aware targeting to suppress immune dysregulation without promoting ossification. This synthesis integrates molecular, cellular, and translational insights into a unified model of AS pathogenesis. By aligning mechanistic disruption with stage-specific and exosome-enabled interventions, it establishes a conceptual foundation for precision therapies aimed at recalibrating immune\u2013stromal interactions and halting structural progression. This review synthesizes published mechanistic and translational evidence and includes hypothesis-generating therapeutic concepts that remain to be formally validated in AS.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1738120","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T05:28:42Z","timestamp":1773120522000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Restoring adenosine balance in axial spondyloarthritis: a stage-specific framework for immune and structural modulation"],"prefix":"10.3389","volume":"17","author":[{"given":"Fataneh","family":"Tavasolian","sequence":"first","affiliation":[{"name":"Schroeder Arthritis Institute, Toronto Western Hospital, University Health Network","place":["Toronto, ON, Canada"]},{"name":"Krembil Research Institute, University Health Network","place":["Toronto, ON, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Behdad","family":"Ravarian","sequence":"additional","affiliation":[{"name":"Hand Program, Division of Plastic, Reconstructive and Aesthetic Surgery, Toronto Western Hospital, University Health Network, Department of Surgery, affiliated with Temerty Faculty of Medicine, University of Toronto","place":["Toronto, ON, Canada"]},{"name":"Division of Orthopedics, Osteoarthritis Research Program, Schroeder Arthritis Institute, University Health Network","place":["Toronto, ON, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Lim","sequence":"additional","affiliation":[{"name":"Schroeder Arthritis Institute, Toronto Western Hospital, University Health Network","place":["Toronto, ON, Canada"]},{"name":"Krembil Research Institute, University Health Network","place":["Toronto, ON, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert 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