Innate myeloid immune cells, and neutrophils in particular, serve as first line of defense against pathogenic microorganisms including bacteria and fungi. Given their short life span during ...steady-state conditions, myeloid cells – with, in some cases, the exception of tissue macrophages – need to be constantly regenerated from hematopoietic stem and progenitor cells. During severe systemic bacterial infection, myeloid cell turnover is dramatically increased due to their unique modus operandi in combating invading pathogens involving release of lytic enzymes and neutrophil extracellular traps. Consequently, steady-state hematopoiesis is switched to emergency hematopoiesis by launching a unique hematopoietic response program that is aimed at greatly increasing myeloid cell output to meet the higher demand. In this review, we will discuss well-established as well as recently emerging concepts around the regulation of this fundamental process.
Neutrophils are a key cell type of the innate immune system. They are short-lived and need to be continuously generated in steady-state conditions from haematopoietic stem and progenitor cells in the ...bone marrow to ensure their immediate availability for the containment of invading pathogens. However, if microbial infection cannot be controlled locally, and consequently develops into a life-threatening condition, neutrophils are used up in large quantities and the haematopoietic system has to rapidly adapt to the increased demand by switching from steady-state to emergency granulopoiesis. This involves the markedly increased de novo production of neutrophils, which results from enhanced myeloid precursor cell proliferation in the bone marrow. In this Review, we discuss the molecular and cellular events that regulate emergency granulopoiesis, a process that is crucial for host survival.
Inflammation is an evolutionarily selected defense response to infection or tissue damage that involves activation and consumption of immune cells in order to reestablish and maintain organismal ...integrity. In this process, hematopoietic stem cells (HSCs) are themselves exposed to inflammatory cues and via proliferation and differentiation, replace mature immune cells in a demand-adapted fashion. Here, we review how major sources of systemic inflammation act on and subsequently shape HSC fate and function. We highlight how lifelong inflammatory exposure contributes to HSC inflamm-aging and selection of premalignant HSC clones. Finally, we explore emerging areas of interest and open questions remaining in the field.
Aging is associated with impaired hematopoietic and immune function caused in part by decreased fitness in the hematopoietic stem cell (HSC) population and an increased myeloid differentiation bias. ...The reasons for this aging-associated HSC impairment are incompletely understood. Here we demonstrate that older specific pathogen free (SPF) wild-type (WT) mice in contrast to young SPF mice produce more interleukin-1a and interleukin-1b (IL-1a/b) in steady-state bone marrow (BM), with most of the IL-1a/b being derived from myeloid BM cells. Furthermore, blood from steady-state older SPF WT mice contains higher levels of microbe-associated molecular patterns, specifically TLR4 and TLR8 ligands. In addition, BM myeloid cells from older mice produce more IL-1b in vitro, and older mice show higher and more durable IL-1a/b responses upon stimulation with lipopolysaccharide in vivo. To test whether HSC aging is driven by IL-1a/b, we evaluated HSCs from IL-1 receptor 1 (IL-1R1) knockout (KO) mice. Indeed, older HSCs from IL-1R1KO mice show significantly mitigated aging-associated inflammatory signatures. Moreover, HSCs from older IL-1R1KO and from germ-free mice maintain unbiased lymphomyeloid hematopoietic differentiation upon transplantation, thus resembling this functionality of young HSCs. Importantly, in vivo antibiotic suppression of microbiota or pharmacologic blockade of IL-1 signaling in older WT mice was similarly sufficient to reverse myeloid-biased output of their HSC populations. Collectively, our data define the microbiome/IL-1/IL-1R1 axis as a key, self-sustaining and also therapeutically partially reversible driver of HSC inflammaging.
During systemic infection and inflammation, immune effector cells are in high demand and are rapidly consumed at sites of need. Although adaptive immune cells have high proliferative potential, ...innate immune cells are mostly postmitotic and need to be replenished from bone marrow (BM) hematopoietic stem and progenitor cells. We here review how early hematopoiesis has been shaped to deliver efficient responses to increased need. On the basis of most recent findings, we develop an integrated view of how cytokines, chemokines, as well as conserved pathogen structures, are sensed, leading to divisional activation, proliferation, differentiation, and migration of hematopoietic stem and progenitor cells, all aimed at efficient contribution to immune responses and rapid reestablishment of hematopoietic homeostasis. We also outline how chronic inflammatory processes might impinge on hematopoiesis, potentially fostering hematopoietic stem cell diseases, and, how clinical benefit is and could be achieved by learning from nature.
Dendritic cell homeostasis Merad, Miriam; Manz, Markus G.
Blood,
04/2009, Volume:
113, Issue:
15
Journal Article
Peer reviewed
Open access
Dendritic cells (DCs) are a heterogeneous fraction of rare hematopoietic cells that coevolved with the formation of the adaptive immune system. DCs efficiently process and present antigen, move from ...sites of antigen uptake to sites of cellular interactions, and are critical in the initiation of immune responses as well as in the maintenance of self-tolerance. DCs are distributed throughout the body and are enriched in lymphoid organs and environmental contact sites. Steady-state DC half-lives account for days to up to a few weeks, and they need to be replaced via proliferating hematopoietic progenitors, monocytes, or tissue resident cells. In this review, we integrate recent knowledge on DC progenitors, cytokines, and transcription factor usage to an emerging concept of in vivo DC homeostasis in steady-state and inflammatory conditions. We furthermore highlight how knowledge of these maintenance mechanisms might impact on understanding of DC malignancies as well as posttransplant immune reactions and their respective therapies.
Monocytes and macrophages are critical effectors and regulators of inflammation and the innate immune response, the immediate arm of the immune system. Dendritic cells initiate and regulate the ...highly pathogen-specific adaptive immune responses and are central to the development of immunologic memory and tolerance. Recent in vivo experimental approaches in the mouse have unveiled new aspects of the developmental and lineage relationships among these cell populations. Despite this, the origin and differentiation cues for many tissue macrophages, monocytes, and dendritic cell subsets in mice, and the corresponding cell populations in humans, remain to be elucidated.
All hematopoietic and immune cells are continuously generated by hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) through highly organized process of stepwise lineage ...commitment. In the steady state, HSCs are mostly quiescent, while HPCs are actively proliferating and contributing to daily hematopoiesis. In response to hematopoietic challenges, e.g., life-threatening blood loss, infection, and inflammation, HSCs can be activated to proliferate and engage in blood formation. The HSC activation induced by hematopoietic demand is mediated by direct or indirect sensing mechanisms involving pattern recognition receptors or cytokine/chemokine receptors. In contrast to the hematopoietic challenges with obvious clinical symptoms, how the aging process, which involves low-grade chronic inflammation, impacts hematopoiesis remains undefined. Herein, we summarize recent findings pertaining to functional alternations of hematopoiesis, HSCs, and the bone marrow (BM) microenvironment during the processes of aging and inflammation and highlight some common cellular and molecular changes during the processes that influence hematopoiesis and its cells of origin, HSCs and HPCs, as well as the BM microenvironment. We also discuss how age-dependent alterations of the immune system lead to subclinical inflammatory states and how inflammatory signaling might be involved in hematopoietic aging. Our aim is to present evidence supporting the concept of "Inflamm-Aging," or inflammation-associated aging of hematopoiesis.
Hematopoietic stem cells in mammals are known to reside mostly in the bone marrow, but also transitively passage in small numbers in the blood. Experimental findings have suggested that they exist in ...a dynamic equilibrium, continuously migrating between these two compartments. Here we construct an individual-based mathematical model of this process, which is parametrised using existing empirical findings from mice. This approach allows us to quantify the amount of migration between the bone marrow niches and the peripheral blood. We use this model to investigate clonal hematopoiesis, which is a significant risk factor for hematologic cancers. We also analyse the engraftment of donor stem cells into non-conditioned and conditioned hosts, quantifying the impact of different treatment scenarios. The simplicity of the model permits a thorough mathematical analysis, providing deeper insights into the dynamics of both the model and of the real-world system. We predict the time taken for mutant clones to expand within a host, as well as chimerism levels that can be expected following transplantation therapy, and the probability that a preconditioned host is reconstituted by donor cells.
Hematopoietic stem and progenitor cell-derived neoplasia is challenging to target by cell surface-directed immunotherapy due to lack of tumor cell-specific antigen identification. Marone et al. ...(2023. J. Exp. Med.https://doi.org/10.1084/jem.20231235) provide a solution by target-epitope resistance editing in healthy hematopoietic stem cells.
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