PhysiologicalControl ofImmuneResponse andInflammatoryTissueDamage byHypoxia-InducibleFactors andAdenosineA_2AReceptors

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 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.

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

“…It remains to be tested if A 2A R in myeloid cells also play a key role in other brain noxious conditions where the infiltration of these cells into the brain is less well documented. This proposal that the effect of A 2A Rs in myeloid cells is most important for the role of A 2A Rs in the control of brain damage is surprising based on the well established robust role of adenosine in attenuating (rather than exacerbating) inflammation in the periphery ( [294]; reviewed in [295,296]). In fact, adenosine is a potent anti-inflammatory agent with A 2A Rs triggering BOFF^signals in activated immune cells, which constitutes one of the most fundamental and immediate tissue-protecting mechanisms (reviewed in [295,296]).…”

Pleural fluid from tuberculous pleurisy inhibits the functions of T cells and the differentiation of Th1 cells via immunosuppressive factors

“…27 At the height of inflammation, the destruction of host tissue combined with damaged microcirculation and hypoxia leads to elevation of extracellular adenosine. 28 Animal models of asthma, 29 arthritis, 30 sepsis, 31 inflammatory bowel disease 32 and wound healing 33 have helped to elucidate the regulatory roles of adenosine in dictating the development and progression of disease.…”

Tumor-targeting prodrug-activating bacteria for cancer therapy

“…For example, Griffioen et al indicated that tumors downregulate vascular cell adhesion molecule-1 expression on endothelial cells, which modulate immune cells-vessel wall interaction and decrease the effector's cells to enter tumor tissue. 16 Sitkovsky et al 17 showed that hypoxia-induced adenosine and adenosine receptortriggered signaling can block innate and adaptive immune responses to prevent tissues damage from inflammatory damage and also protect cancerous tissues by inhibiting incoming antitumor T lymphocytes, 28 Le et al showed that a novel hypoxia-induced galectin-1 protein modulates tumor immune privilege in vivo. 29 These results suggest that tumor microenvironment may provide a sanctuary for a small number of bacteria that will escape the immune clearance.…”

“…Systemically administered bacteria selectively replicated at tumor region may be dependent on various tumor-related factors. For example, tumor may release the regulatory cytokines (IL-10, IL-4, TGFb), 12,13 downregulation of Fas or upregulation of FasL expression to escape immune clearance 14,15 reducing the expression of vascular cell adhesion molecule-1 on endothelial cell to prevent immune effector cells to enter tumor tissue 16 and hypoxia-induced adenosine accumulation suppresses the function of activated immune cells 17 to provide an immunosuppressive or hypoxic environment for bacteria to replicate within tumors. Based on these findings, we wished to test whether bacterial delivery of the prodrug-activating enzyme bG could be achieved to allow selective intratumoral activation of a glucuronide prodrug 9ACG for cancer therapy (Figure 1).…”