The role of sirtuin 1 on the induction of trained immunity

Leonie S. Helder,Simone J.C.F.M. Moorlag,Martin Jaeger,Jelmer H. van Puffelen,Charlotte D.C.C. van der Heijden,Leo A.B. Joosten,Samuel T. Keating,Valerie A.C.M. Koeken,Mihai G. Netea,Vasiliki Matzaraki,Vera P. Mourits,Laszlo Groh,L. Charlotte J. de Bree

doi:10.1016/j.cellimm.2021.104393

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.

Highlights

Sirtuins are a family of highly conserved nicotinamide adenine dinucleotide (NAD)+-dependent protein deacetylases
peripheral blood mononuclear cells (PBMCs) were exposed to the synthetic Sirtuin 1 (SIRT1) inhib itor EX-527 at various concentrations (1–100 μM), and stimulated for 24 h with TLR4 ligand LPS or TLR1/2 ligand Pam3Cys
We show that genetic variation in SIRT1 in fluences the induction of inflammation as reflected by cytokine pro duction upon stimulation of PBMCs, as well as the induction of trained immunity in an in vitro experimental model

Summary

Introduction

Sirtuins are a family of highly conserved nicotinamide adenine dinucleotide (NAD)+-dependent protein deacetylases. The mammalian sirtuin family consists of seven proteins (SIRT1-7), which are involved in a variety of cellular processes including cell differentiation, metabolism, and stress responses [1,2]. Most studies show that acute inflammation decreases the expression level of SIRT1, which leads to a pro-inflammatory response [4,5,6,7]. This can occur via the deacetylation of NF-κB subunit RelA/p65, or indirectly by inducing repressive transcriptional complexes [3,8]. SIRT1 is able to deacetylate H1 histones at lysine (K) 26, as well as H3 histones at lysine 9 (H3K9), lysine 14 (H3K14), and H4 histones at lysine 16 (H4K16) [9,11,12], this results in pleiotropic effects

Methods

Results

Conclusion