Trained innate immunity, long-lasting epigenetic modulation, and skewed myelopoiesis by heme

TLDR

Extracellular heme released during infection acts as an alarmin that activates myeloid cells, and such activation is associated with trained immunity driven by long‑lasting transcriptional and epigenetic changes that are maintained through altered hematopoiesis. The study proposes that trained immunity constitutes a broader component of innate immunity than previously recognized, given heme’s pivotal role during infections. In mice, heme was shown to induce trained immunity that enhances resistance to bacterial infection, accompanied by persistent epigenetic reprogramming of hematopoietic stem cells that reshapes transcription factor binding in myeloid progenitors.

Abstract

Significance During infection, extracellular “labile” heme, released from damaged red blood or parenchymal cells, acts as prototypical alarmin stimulating myeloid cells. A characteristic hallmark of myeloid cell activation is the development of trained immunity, specified as long-lasting adaptations based on transcriptional and epigenetic modifications. In vivo, this is maintained by the rerouting of hematopoiesis. We found that heme is a previously unrecognized trained immunity inducer promoting resistance to bacterial infection in mice. This goes along with extensive long-lasting epigenetic memory in hematopoietic stem cells provoking drastic changes in the transcription factor–binding landscape of myeloid progenitor cells. Given the critical role of heme during infections, we propose that trained immunity is a more general component of innate immunity than previously suggested.