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Damage control by hypoxia-inhibited AK

Michail V. Sitkovsky

HIF-1α represses adenosine kinase, thereby enabling hypoxia-driven adenosinergic tissue protection.

Hypoxia can be both tissue-protecting and tissue-damaging. Indeed, hypoxic exposure in the mountains' death zone causes leakage of fluid from the intravascular space into the surrounding tissue, leading to severe brain or lung edema. In contrast, tissue hypoxia due to excessive inflammatory collateral damage during immune response protects tissue by preventing the leakage of intravascular fluid that might otherwise lead to conditions such as inflamed lung. The protection is mediated by the collaborating activities of hypoxia-inducible factor-1α (HIF-1α), extracellular adenosine, and A2 adenosine receptors.1,2 But what is the exact molecular machinery that translates the hypoxic signal into elevation of extracellular adenosine, which then triggers tissue-protecting A2 adenosine receptors?

An important finding that fits the cogent model of hypoxic regulation of tissue damage is described by Morote-Garcia and coauthors in this issue of Blood. Their study yielded the exciting observation that it is the ubiquitous HIF-1α3 that is responsible for transcriptional repression of endothelial adenosine kinase (AK). The inhibition of AK prevents rapid conversion of intracellular adenosine to adenosine monophosphate, and this was shown in isolated heart models to potentiate extracellular adenosine accumulation.4 Thus, Morote-Garcia and coworkers provide previously missing evidence of the mechanism whereby (1) pathological hypoxia stabilizes HIF-1α; (2) HIF-1α inhibits AK; and (3) inhibition of AK results in accumulation of extracellular adenosine that triggers (4) tissue-protecting signaling via A2 adenosine receptors.1,2

In addition, tissue-protecting hypoxia and HIF-1α up-regulate adenosine-generating ectoenzymes CD39 and CD73 on the vascular surface, induce adenosine receptor expression, and repress adenosine uptake and adenosine metabolism, all of which enhance extracellular adenosine-dependent tissue protection during hypoxia (reviewed in Sitkovsky et al1 and the current article).

Future studies should establish the proportional contribution to A2 adenosinergic tissue protection of (1) HIF-1α–mediated increases in levels of extracellular adenosine produced by ectoenzymes CD39 and CD73 as compared with (2) HIF-1α–mediated increases in intracellular levels of adenosine due to AK inhibition as described in this issue of Blood. Because high levels of intracellular adenosine could be toxic, as is the case during severe adenosine deaminase immunodeficiency, the overall effect of adenosine kinase inhibition may also include increased release of intracellular adenosine into the extracellular compartment. This will accomplish both protection of cells from toxic intracellular adenosine metabolites and A2-receptor–mediated signaling by extracellular adenosine to protect tissues from continuing damage.

It is appealing to propose that hypoxia- and TCR-triggered increases in levels of stabilized I.1 and I.2 HIF-1α isoforms in T cells1 and in T regulatory cells may increase the level of T regulatory cell–generated immunosuppressive extracellular adenosine due to (1) HIF-1α–up-regulated CD39/CD73 ectoenzymes and (2) inhibition of AK by HIF-1α as described here. This, in turn, will further strengthen hypoxic tissue protection.

Footnotes

  • Conflict-of-interest disclosure: The author declares no competing financial interests. ■

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