PhysiologicalControl ofImmuneResponse andInflammatoryTissueDamage byHypoxia-InducibleFactors andAdenosineA2AReceptors

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Abstract
▪ Abstract Immune cell–mediated destruction of pathogens may result in excessive collateral damage to normal tissues, and the failure to control activated immune cells may cause immunopathologies. The search for physiological mechanisms that downregulate activated immune cells has revealed a critical role for extracellular adenosine and for immunosuppressive A2Aadenosine receptors in protecting tissue from inflammatory damage. Tissue damage–associated deep hypoxia, hypoxia-inducible factors, and hypoxia-induced accumulation of adenosine may represent one of the most fundamental and immediate tissue-protecting mechanisms, with adenosine A2Areceptors triggering “OFF” signals in activated immune cells. In these regulatory mechanisms, oxygen deprivation and extracellular adenosine accumulation serve as “reporters,” while A2Aadenosine receptors serve as “sensors” of excessive tissue damage. The A2Areceptor–triggered generation of intracellular cAMP then inhibits activated immune cells in a delayed negative feedback manner to prevent additional tissue damage. Targeting A2Aadenosine receptors may have important clinical applications.