Modulation of Myelopoiesis Progenitors Is an Integral Component of Trained Immunity

Abstract

SummaryTrained innate immunity fosters a sustained favorable response of myeloid cells to a secondary challenge, despite their short lifespan in circulation. We thus hypothesized that trained immunity acts via modulation of hematopoietic stem and progenitor cells (HSPCs). Administration of β-glucan (prototypical trained-immunity-inducing agonist) to mice induced expansion of progenitors of the myeloid lineage, which was associated with elevated signaling by innate immune mediators, such as IL-1β and granulocyte-macrophage colony-stimulating factor (GM-CSF), and with adaptations in glucose metabolism and cholesterol biosynthesis. The trained-immunity-related increase in myelopoiesis resulted in a beneficial response to secondary LPS challenge and protection from chemotherapy-induced myelosuppression in mice. Therefore, modulation of myeloid progenitors in the bone marrow is an integral component of trained immunity, which to date, was considered to involve functional changes of mature myeloid cells in the periphery.

Western Diet Triggers NLRP3-Dependent Innate Immune Reprogramming

“…Our study, together with work by Mitroulis et al (2018 [this issue of Cell ]) in this issue of Cell , implies that an inflammasome-mediated product, such as IL-1β, is likely the central endogenous mediator of the mechanisms resulting in the induction of trained immunity. Indeed, early work had already established that injections of IL-1β before experimental infection can prevent lethality from infections (van der Meer et al, 1988).…”

“…The work by the International Trained Immunity Consortium (INTRIM), reported in this issue of Cell now demonstrates that trained immunity can be induced on the level of HSPCs. Mitroulis et al (2018 [this issue of Cell ]) show that the trained immunity model ligand β-glucan induces metabolic and transcriptional rewiring in HSPCs through IL-1R signaling, which protects the hematopoietic system from chemotherapy-induced myeloablation.…”

HIV vaccine candidate activation of hypoxia and the inflammasome in CD14+ monocytes is associated with a decreased risk of SIVmac251 acquisition

“…ALVAC preferentially infects CD14 + cells 28 and induces 50-fold higher levels of IL-1β within 24 h of immunization than does Ad26 (refs 41,42 ) (Supplementary Table 6). This early burst of IL-1β, a cytokine that is tightly regulated by the inflammasome, may provide the ‘emergency’ signal 43 that is necessary for engagement of the myeloid compartment and the generation of a memory innate response following ALVAC immunization. This is a well-characterized phenomenon in which hypoxia and inflammasome activation in monocytes causes a metabolic switch from oxidative phosphorylation to glycolysis, epigenetic reprogramming that results either in increased (training) or decreased (tolerance) cytokine and chemokine responsiveness upon restimulation 43–46 and involves several cellular pathways, including RAS.…”

“…This early burst of IL-1β, a cytokine that is tightly regulated by the inflammasome, may provide the ‘emergency’ signal 43 that is necessary for engagement of the myeloid compartment and the generation of a memory innate response following ALVAC immunization. This is a well-characterized phenomenon in which hypoxia and inflammasome activation in monocytes causes a metabolic switch from oxidative phosphorylation to glycolysis, epigenetic reprogramming that results either in increased (training) or decreased (tolerance) cytokine and chemokine responsiveness upon restimulation 43–46 and involves several cellular pathways, including RAS. Future studies on the CD14 + monocytes epigenome will be needed to clarify the nature (training or tolerance) and duration of the innate immunity elicited by the DNA–ALVAC-gp120 vaccine platform.…”

Two to Tango: Dialog between Immunity and Stem Cells in Health and Disease

“…These trained HSCs and myeloid progenitors were able to more efficiently ward off inflammatory challenges when compared to naïve HSCs. Intriguingly, IL-1β-trained HSCs exhibited dramatic changes in their energy metabolism, displaying augmented glycolysis and cholesterol biosynthesis, adjustments that turned out to be critical for conferring downstream functional changes in β-glucan-dependent HSC training (Figure 4B) (Mitroulis et al, 2018). …”