Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors.
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 A2A adenosine 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 A2A receptors triggering "OFF" signals in activated immune cells. In these regulatory mechanisms, oxygen deprivation and extracellular adenosine accumulation serve as "reporters," while A2A adenosine receptors serve as "sensors" of excessive tissue damage. The A2A receptor-triggered generation of intracellular cAMP then inhibits activated immune cells in a delayed negative feedback manner to prevent additional tissue damage. Targeting A2A adenosine receptors may have important clinical applications.
Sitkovsky
Michail V
MV
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Building 10, Room 11N256, National Institutes of Health, Bethesda, Maryland 20892, USA. msitkov@helix.nih.gov
Lukashev
Dmitriy
D
Apasov
Sergey
S
Kojima
Hidefumi
H
Koshiba
Masahiro
M
Caldwell
Charles
C
Ohta
Akio
A
Thiel
Manfred
M
D000241:Adenosine / Q000276:immunology; D000818:Animals; D004268:DNA-Binding Proteins / Q000276:immunology*; D006801:Humans; D000860:Hypoxia / Q000276:immunology / Q000503:physiopathology; D007111:Immunity, Cellular; D007249:Inflammation / Q000276:immunology*; D009687:Nuclear Proteins / Q000276:immunology*; D043683:Receptors, Adenosine A2 / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D043683:Receptors, Adenosine A2; D000241:Adenosine