Modulation of Myelopoiesis Progenitors Is an Integral Component of Trained Immunity

TLDR

Trained innate immunity sustains a favorable response of short‑lived myeloid cells to secondary challenges, and recent evidence shows that modulation of bone‑marrow myeloid progenitors is a core component of this process. The study hypothesizes that trained immunity operates through modulation of hematopoietic stem and progenitor cells. β‑glucan treatment in mice expanded myeloid progenitors, accompanied by increased IL‑1β and GM‑CSF signaling and shifts in glucose metabolism and cholesterol biosynthesis. Enhanced myelopoiesis conferred a stronger response to secondary LPS challenge and protected mice from chemotherapy‑induced myelosuppression.

Abstract

Trained 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.