Metabolic Induction of Trained Immunity through the Mevalonate Pathway

Abstract

Innate immune cells can develop long-term memory after stimulation by microbial products during infections or vaccinations. Here, we report 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.

Western Diet Triggers NLRP3-Dependent Innate Immune Reprogramming

“…Additionally, cholesterol overload in hematopoietic progenitors could also lead to a sustained state of intracellular stress, linked to increased inflammatory signaling and a potential long-term reprogramming. Supportively, the studies by Bekkering et al (2018 [this issue of Cell ]) reported in this issue of Cell show that dysbalanced cholesterol biosynthesis with an accumulation of mevalonate can drive trained immunity induction. On the other hand, it appears plausible that NLRP3 could also instigate inflammatory pathologies toward a range of sterile danger signals not limited to WD, as numerous triggers of relevance in human chronic inflammatory pathologies have been linked to NLRP3 activation (Heneka et al, 2013; Hornung et al, 2008; Martinon et al, 2006).…”

Urate‐induced immune programming: Consequences for gouty arthritis and hyperuricemia

“…Glutaminolysis represents another metabolic reconfiguration observed in immune training of cells with β‐glucan, and inhibition of this metabolic shift leads to reduced induction of trained immunity in vivo . Similarly altered immune states with enhanced inflammatory cytokine production associated with epigenetic modifications have not only been observed in settings using microbial stimulations, but also in response to sterile ligands such as oxLDL or hypercholesterolemia in the context of atherosclerosis …”

Immune modulatory effects of statins

“…An important novel observation is that statins also impact the immune system through effects on immune cell metabolism. Recently a study showed that activation of the cholesterol synthesis pathway was essential for immunological training of myeloid immune cells . The study also reported that the metabolite mevalonate is the mediator of training through activation of insulin‐like growth factor 1 receptor and mammalian target of rapamycin and subsequent histone modifications in inflammatory pathways .…”