The role of sirtuin 1 on the induction of trained immunity
Vera P. Mourits, Leonie Helder, Vasiliki Matzaraki, Valerie A. C. M. Koeken, Laszlo Groh, L. Charlotte J. de Bree, Simone J.C.F.M. Moorlag, Charlotte D.C.C. van der Heijden, Samuel T. Keating, Jelmer H. van Puffelen, Martin Jaeger, Leo A. B. Joosten, Mihai G. Netea
Abstract
Sirtuin 1 (SIRT1) has been described to modify immune responses by modulation of gene transcription. As transcriptional reprogramming is the molecular substrate of trained immunity, a de facto innate immune memory, we investigated the role of SIRT1 in the induction of trained immunity. We identified various SIRT1 genetic single nucleotide polymorphisms affecting innate and adaptive cytokine production of human peripheral blood mononuclear cells (PBMCs) in response to various stimuli on the one hand, and in vitro induction of trained immunity on the other hand. Furthermore, inhibition of SIRT1 upregulated pro-inflammatory innate cytokine production upon stimulation of PBMCs. However, inhibition of SIRT1 in vitro had no effect on cytokine responses upon induction of trained immunity, while activation of SIRT1 mildly modified trained immunity responses. In conclusion, SIRT1 modifies innate cytokine production by PBMCs in response to various microbes, but has only a secondary role for BCG and β-glucan-induced trained immunity responses.