Cell paper published by the Radboud and Cluj-Napoca groups on the cholesterol synthesis pathway,

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Bekkering et al (2018) published their groundbreaking results on the cholesterol synthesis pathway, and in particular the intermediate mevalonate. This pathway is essential for inducing trained innate immunity, the key-concept of REPROGRAM.

Highlights

  • Induction of trained immunity by beta-glucan depends on intracellular mevalonate
  • Mevalonate induces trained immunity in human monocytes
  • Mevalonate-induced training is mediated through increased function of IGF1 receptor
  • Monocytes of HIDS patients (that accumulate mevalonate) have a trained phenotype

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Innate immune cells can develop long-term memory after stimulation by microbial products during infections or vaccinations. Here, it is reported that metabolic signals can induce trained immunity. Pharmacological and genetic experiments reveal that activation of the cholesterol synthesis pathway, but not the synthesis of cholesterol itself, is essential for training of myeloid cells. Rather, the metabolite mevalonate is the mediator of training via activation of IGF1-R and mTOR and subsequent histone modifications in inflammatory pathways. Statins, which block mevalonate generation, prevent trained immunity induction. Furthermore, monocytes of patients with hyper immunoglobulin D syndrome (HIDS), who are mevalonate kinase deficient and accumulate mevalonate, have a constitutive trained immunity phenotype at both immunological and epigenetic levels, which could explain the attacks of sterile inflammation that these patients experience. Unraveling the role of mevalonate in trained immunity contributes to our understanding of the pathophysiology of HIDS and identifies novel therapeutic targets for clinical conditions with excessive activation of trained immunity.

 

This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement N°667837.