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

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.
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.