![]() Alarmins can signal via PRR as well as other receptors to promote inflammatory responses. While PRR likely evolved to recognize PAMPs expressed by microbes 27, these can also sense a number of endogenous molecules, designated originally as damage-associated molecular patterns (DAMP) 28, 29 or alarmins 9. It can be initiated at the level of hematopoietic stem and progenitor cells (HSPC), associated with increased myelopoiesis 25, 26. Trained immunity was originally demonstrated to occur in monocytes and Mφ and later on in other cell types, such as Natural Killer (NK) cells 22, 23 or epithelial stem cells 24. However, depending on the stimulating component, it can also result in an enhanced inflammatory response upon restimulation which is then referred to as trained immunity or innate immune memory. This contributes to the long-known phenomenon of LPS tolerance 15, 21. The deposition of epigenetic marks on histone tails, poising target genes for transcriptional activation or repression in response to PRR signaling by PAMPs 18, 19. This is perceived as part of an evolutionarily conserved host defense strategy against infections caused by different pathogens 18– 20. It is now well established that certain pathogen associated molecular patterns (PAMPs), such as LPS, fungal β-glucan or certain vaccines can induce long-lasting epigenetic and transcriptional modifications in myeloid cells 15– 18. Also depending on dosage and timing of administration, heme can exert protective effects against a variety of other immune-mediated inflammatory diseases 14. Of note, chronic low-dose cellular exposure to labile heme can exert protective effects via the induction of the heme catabolizing enzyme heme oxygenase-1 (HO-1), underlying exemplarily how sickle cell trait protects against malaria 6. It also induces inflammasome activation in murine macrophages (Mφ) when applied shortly after lipopolysaccharide (LPS) 13. It is an intracellular molecule that is released upon cellular damage and sensed by innate immune cells via different pattern recognition receptors (PRR), including Toll Like Receptor (TLR)-4 and the NOD-like receptor family 11, 12. Labile heme can be considered a prototypical alarmin 9. As such, labile heme acts as a highly pro-oxidant agonists that contributes critically to the pathogenesis of severe infections, as demonstrated for malaria 4– 7 and for bacterial sepsis 8– 10. As it becomes loosely bound to plasma acceptor proteins or macromolecules, these reduce but do not prevent labile heme redox activity that underlies its pathological effects 2, 3. Hemolysis or other forms of tissue damage can cause accumulation of cell-free labile heme in plasma 2. Heme is an iron-containing protoporphyrin that acts as a prosthetic group in vital hemoproteins 1. In conclusion, we reveal that heme, a bona fide alarmin, induces innate immune memory regulating host response to infection. Finally, heme-induced training was protective against bacterial sepsis in mice. Heme training in mice was associated with long-lasting expansion of myeloid-biased progenitor cells as well as with altered chromatin accessibility in hematopoietic stem and progenitor cells. In sharp contrast to β-glucan training however, heme-training relied on activation of the Syk/JNK-pathway. Heme-trainning in monocytes is associated with epigenetic and transcriptional profiles that overlap to some extent with those seen in β-glucan-training, the prototype agonist of trained immunity. Here, we report that labile heme, an alarmin released extracellularily upon tissue damage and hemolysis, induces trained immunity in human and murine primary cells and in mice. Trained immunity defines long-lasting adaptive responses of innate immunity, mediated by transcriptional and epigenetic modifications of myeloid cells. ![]()
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