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.

受过训练的免疫定义了基于骨髓细胞及其骨髓祖细胞的转录和表观遗传修饰的先天免疫的长期适应性 [M. Divangahi 等人，Nat。免疫学。22, 2-6 (2021)]。然而，先天免疫细胞并不完全区分外来和自身，而且还会对宿主衍生的称为警报素的分子起反应。感染期间释放的细胞外“不稳定”血红素是一种真正的警报，可促进骨髓细胞活化 [MP Soares, MT Bozza, Curr. 意见。免疫学。38, 94–100 (2016)]。在这里，我们报告说，不稳定的血红素是一种以前未被认识的训练免疫诱导剂，它赋予造血干细胞和祖细胞谱系规范的长期调节。与之前关于受过训练的免疫（主要由病原体相关分子模式介导）的报告相反，血红素训练依赖于作用于 c-Jun N 端激酶上游的脾酪氨酸激酶信号转导通路。血红素训练促进对败血症的抵抗力，与自我更新的造血干细胞的扩增相关，这些干细胞已准备好向骨髓细胞生成和特定骨髓细胞群的发生。这可能是由 Nfix、Runx1 和 Nfe2l2 的持续活性以及转录抑制因子 Bach2 的解离引起的。然而，先前报道的训练有素的免疫诱导剂是 很少存在于宿主中，而血红素在非传染性疾病和传染性疾病中大量出现。这种差异可能解释了血红素训练在脓毒症中随着时间的推移与持续的长期骨髓适应所发挥的保护作用。因此，我们认为训练有素的免疫是先天免疫的一个组成部分，根据病原体或内源性分子的诱导，在传染病结果上具有明显的功能差异。