Immunometabolic effects of vitamin D unravelled by an integrative systems biology analysis: A collaborative bioinformatics and laboratory approach

This thesis is the result of a joint collaboration between research institutes with expertise in two distinct aspects of science: cell biology and bioinformatics. By using state of the art techniques from both of these fields the thesis describes the discovery of an entirely new role for vitamin D in the immune system, as a potent regulator of immunometabolism. To demonstrate this, the project initially focused on bioinformatic analyses in which we developed applied computational techniques to interrogate publically available transcriptomic datasets generated in studies of the immunomodulatory effects of the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Using this bioinformatic approach we were able to demonstrate that the predominant effect of 1,25(OH)2D3 on myeloid derived innate immune cells such as monocytes and dendritic cells (DC) was to regulate cell metabolism via enhanced glycolysis, electron transport, oxidative phosphorylation and TCA cycle activity. In the second half of this thesis, we have explored the immunometabolic function of 1,25(OH)2D3 further through in vitro experiments that investigated the specific function of immunometabolism in mediating the tolerogenic effects of 1,25(OH)2D3 on DC. The overall conclusion from these cellular experiments was that the ability of 1,25(OH)2D3 to promote anti-inflammatory tolerogenic innate immune responses by DC is crucially dependent on the regulation of cell metabolism rather than specific immune actions. This new perspective on the immunomodulatory actions of vitamin D may help to identify new strategies for the therapeutic use of vitamin D in the treatment of inflammatory disease.