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

Elisa Jentho, Cristian Ruiz-Moreno, Boris Novakovic, Ioannis Kourtzelis, Wout L. Megchelenbrink, Rui Martins, Triantafyllos Chavakis, Miguel P. Soares, Lydia Kalafati, Joel Guerra, Franziska Roestel, Peter Bohm, Maren Godmann, Tatyana Grinenko, Anne Eugster, Martina Beretta, Leo A.B. Joosten, Mihai G. Netea, Michael Bauer, Hendrik G. StunnenbergSebastian Weis

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)


Trained immunity defines long-lasting adaptations of innate immunity based on transcriptional and epigenetic modifications of myeloid cells and their bone marrow progenitors [M. Divangahi et al., Nat. Immunol. 22, 2–6 (2021)]. Innate immune cells, however, do not exclusively differentiate between foreign and self but also react to host-derived molecules referred to as alarmins. Extracellular “labile” heme, released during infections, is a bona fide alarmin promoting myeloid cell activation [M. P. Soares, M. T. Bozza, Curr. Opin. Immunol. 38, 94–100 (2016)]. Here, we report that labile heme is a previously unrecognized inducer of trained immunity that confers long-term regulation of lineage specification of hematopoietic stem cells and progenitor cells. In contrast to previous reports on trained immunity, essentially mediated by pathogen-associated molecular patterns, heme training depends on spleen tyrosine kinase signal transduction pathway acting upstream of c-Jun N-terminal kinases. Heme training promotes resistance to sepsis, is associated with the expansion of self-renewing hematopoetic stem cells primed toward myelopoiesis and to the occurrence of a specific myeloid cell population. This is potentially evoked by sustained activity of Nfix, Runx1, and Nfe2l2 and dissociation of the transcriptional repressor Bach2. Previously reported trained immunity inducers are, however, infrequently present in the host, whereas heme abundantly occurs during noninfectious and infectious disease. This difference might explain the vanishing protection exerted by heme training in sepsis over time with sustained long-term myeloid adaptations. Hence, we propose that trained immunity is an integral component of innate immunity with distinct functional differences on infectious disease outcome depending on its induction by pathogenic or endogenous molecules.

Original languageEnglish
Article numbere2102698118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number42
Publication statusPublished - 19 Oct 2021


  • Heme
  • Myelopoiesis
  • Sepsis
  • Single-nuclei analysis
  • Trained innate immunity


Dive into the research topics of 'Trained innate immunity, long-lasting epigenetic modulation, and skewed myelopoiesis by heme'. Together they form a unique fingerprint.

Cite this