Crucial involvement of xanthine oxidoreductase in the biological responses of myeloid hematopoietic cells

Xanthine oxidoreductase (XOR) is one of the main purine catabolising enzymes which converts hypoxanthine into xanthine and further into uric acid. The enzyme has a homodimeric structure and contains two FeS centres, one FAD molecule and one molybdenum atom per monomer. Recent evidence clearly demonstrated that XOR activity is highly increased in human hematopoietic cells of myeloid lineage during their pathogen-induced and endogenously generated biological responses. The integrative signalling role and especially involvement of XOR in cross-talk of metabolic and signalling machinery of human leukocytes remains poorly understood.

We have demonstrated that XOD is activated in human myeloid cells in response to pro-inflammatory and growth factor stimulation. Hypoxia-inducible factor 1 (HIF-1) and activator protein 1 (AP1) transcription complexes were found responsible for maintaining XOR catalytic activity and protein levels. Importantly, the mammalian target of rapamycin (mTOR), a major myeloid cell translation regulator, appeared to be essential for XOR activation. Specific inhibition of XOR led to an increase in intracellular AMP levels triggering downregulation of mTOR activation. Taken together, these results show that XOD is not only activated by pro-inflammatory stimuli or SCF (growth factors), but also plays a crucial role in maintaining mTOR-dependent translational control during the biological responses of hematopoietic cells of myeloid lineage.

Findings reported in this thesis open a new field in human myeloid cell research and translational medicine. XOR is an easily accessible therapeutic target, which could be pharmacologically corrected using non-toxic drugs.