Trained immunity and epigenetic memory in long-term self-renewing hematopoietic cells.

Immunologic memory is a feature typically ascribed to the adaptive arm of the immune system. However, recent studies have demonstrated that hematopoietic stem cells (HSCs) and innate immune cells such as monocytes and macrophages can gain epigenetic signatures to enhance their response in the context of reinfection. This suggests the presence of long-term memory, a phenomenon referred to as trained immunity. Trained immunity in HSCs can occur via changes in the epigenetic landscape and enhanced chromatin accessibility in lineage-specific genes, as well as through metabolic alterations. These changes can lead to a skewing in lineage bias, particularly enhanced myelopoiesis and the generation of epigenetically modified innate immune cells that provide better protection against pathogens on secondary infection. Here, we summarize recent advancements in trained immunity and epigenetic memory formation in HSCs and self-renewing alveolar macrophages, which was the focus of the Spring 2022 International Society for Experimental Hematology (ISEH) webinar.

Johansson A ，Lin DS ，Mercier FE ，Yamashita M ，Divangahi M ，Sieweke MH ... -  《-》

Advances in understanding molecular regulation of innate immune memory.

Domínguez-Andrés J ，Fanucchi S ，Joosten LAB ，Mhlanga MM ，Netea MG ... -  《-》

Discovering adaptive features of innate immune memory.

Conventionally, it was thought that innate immunity operated through a simple system of nonspecific responses to an insult. However, this perspective now seems overly simplistic. It has become evident that intricate cooperation and networking among various cells, receptors, signaling pathways, and protein complexes are essential for regulating and defining the overall activation status of the immune response, where the distinction between innate and adaptive immunity becomes ambiguous. Given the evolutionary timeline of vertebrates and the success of plants and invertebrates which depend solely on innate immunity, immune memory cannot be considered an innovation of only the lymphoid lineage. Indeed, the evolutionary innate immune memory program is a conserved mechanism whereby innate immune cells can induce a heightened response to a secondary stimulus due to metabolic and epigenetic reprogramming. Importantly, the longevity of this memory phenotype can be attributed to the reprogramming of self-renewing hematopoietic stem cells (HSCs) in the bone marrow, which is subsequently transmitted to lineage-committed innate immune cells. HSCs reside within a complex regulated network of immune and stromal cells that govern their two primary functions: self-renewal and differentiation. In this review, we delve into the emerging cellular and molecular mechanisms as well as metabolic pathways of innate memory in HSCs, which harbor substantial therapeutic promise.

Sadeghi M ，Divangahi M 《-》

C/EBPβ-Dependent Epigenetic Memory Induces Trained Immunity in Hematopoietic Stem Cells.

Hematopoietic stem cells (HSCs) maintain life-long production of immune cells and can directly respond to infection, but sustained effects on the immune response remain unclear. We show that acute immune stimulation with lipopolysaccharide (LPS) induced only transient changes in HSC abundance, composition, progeny, and gene expression, but persistent alterations in accessibility of specific myeloid lineage enhancers occurred, which increased responsiveness of associated immune genes to secondary stimulation. Functionally, this was associated with increased myelopoiesis of pre-exposed HSCs and improved innate immunity against the gram-negative bacterium P. aeruginosa. The accessible myeloid enhancers were enriched for C/EBPβ targets, and C/EBPβ deletion erased the long-term inscription of LPS-induced epigenetic marks and gene expression. Thus, short-term immune signaling can induce C/EBPβ-dependent chromatin accessibility, resulting in HSC-trained immunity, during secondary infection. This establishes a mechanism for how infection history can be epigenetically inscribed in HSCs as an integral memory function of innate immunity.

de Laval B ，Maurizio J ，Kandalla PK ，Brisou G ，Simonnet L ，Huber C ，Gimenez G ，Matcovitch-Natan O ，Reinhardt S ，David E ，Mildner A ，Leutz A ，Nadel B ，Bordi C ，Amit I ，Sarrazin S ，Sieweke MH ... -  《-》

Epigenetic Memories in Hematopoietic Stem and Progenitor Cells.

Aoyama K ，Itokawa N ，Oshima M ，Iwama A ... -  《Cells》