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Review
. 2019 Jul;20(7):802-811.
doi: 10.1038/s41590-019-0402-5. Epub 2019 Jun 18.

Hematopoietic progenitor cells as integrative hubs for adaptation to and fine-tuning of inflammation

Triantafyllos Chavakis  1 , Ioannis Mitroulis  2   3   4 , George Hajishengallis  5
Affiliations
Review

Hematopoietic progenitor cells as integrative hubs for adaptation to and fine-tuning of inflammation

Triantafyllos Chavakis et al. Nat Immunol. 2019 Jul.

Abstract

Recent advances have highlighted the ability of hematopoietic stem and progenitor cells in the bone marrow to sense peripheral inflammation or infection and adapt through increased proliferation and skewing toward the myeloid lineage. Such adaptations can meet the increased demand for innate immune cells and can be beneficial in response to infection or myeloablation. However, the inflammation-induced adaptation of hematopoietic and myeloid progenitor cells toward enhanced myelopoiesis might also perpetuate inflammation in chronic inflammatory or cardio-metabolic diseases by generating a feed-forward loop between inflammation-adapted hematopoietic progenitor cells and the inflammatory disorder. Sustained adaptive responses of progenitor cells in the bone marrow can also contribute to trained immunity, a non-specific memory of earlier encounters that in turn facilitates the heightened response of these cells, as well as that of their progeny, to future challenges. Here we discuss the mechanisms that govern the adaptation of hematopoietic progenitor cells to inflammation and its sequelae in the pathogenesis of human disease.

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Figures

Figure 1.
Figure 1.. Inflammatory adaptation of hematopoietic progenitors.
Hematopoietic stem cells (HSC) and multipotent progenitors (MPP) express Toll-like receptors (TLR) sensing directly pathogen-derived products, such as LPS, which can drive HSC proliferation. LPS also stimulates release of cytokines, such as IL-6, from MPPs; IL-6 acts in a paracrine manner to promote HSC proliferation and enhanced myelopoiesis. In parallel, LPS stimulates release of G-CSF from endothelial cells. G-CSF acts on myeloid progenitors, especially on granulocyte macrophage progenitors (GMP) driving their differentiation towards granulocytes. In the course of infection, M-CSF can act direcly on HSCs, promoting their myeloid differentiation, and on GMPs to promote monocyte generation. IFN-α, produced in response to viral infections, induces HSC cell-cycle entry at the expense of their self-renewal potential. IFN-γ, produced in the course of mycobacterial infection, results in HSC proliferation and their instruction towards the myeloid lineage. Release of IL-1 during infection or inflammation drives proliferation and myeloid differentiation of HSCs. Trained immunity induced by β-glucan drives the proliferation and sustained myeloid bias in HSCs through IL-1 and GM-CSF. Trained immunity mediates a beneficial response of HSCs to secondary challenges, such as chemotherapy and LPS administration. Additionally, trained immunity induced by BCG reprograms HSCs resulting in the generation of macrophages with enhanced anti-mycobacterial properties.
Figure 2.
Figure 2.. Regulation of HSCs by their progeny in the BM niche.
Innate and adaptive immune cells in the BM, as well as other HSC progeny, such as megakaryocytes, contribute to HSPC adaptation to inflammatory stimuli derived from systemic infection or inflammation. G-CSF, produced by endothelial cells in response to LPS or systemic infection, acts on myeloid progenitors (MyP) stimulating emergency granulopoiesis, and promotes the egress of HSPCs from the BM. CD169+ macrophages in the BM niche interact with osteoblasts or nestin+ perivascular cells and control their expression of HSC-trophic factors, including CXCL12, which contributes to HSC retention in the niche,. CD169+ macrophages phagocytose apoptotic neutrophils which, upon senescence, home back to the BM; this process promotes the circadian egress of hematopoietic progenitors into the circulation. α-SMA+ macrophages secrete PGE2, which acts on nestin+ cells, which in turn secrete CXCL12, thereby contributing to HSC quiescence and retention. In response to systemic infection or inflammation, Gr1+ myeloid cells in the BM release ROS, which stimulates the expansion and differentiation of MyPs, thus contributing to demand-adapted myelopoiesis. Moreover, under inflammatory conditions, granulocytes in the BM can secrete TNF, which stimulates vessel growth and thus indirectly promotes HSPC regeneration. CD4+CD25+FoxP3+ Treg cells accumulate on the endosteal BM niche and confer immune privilege to the HSC niche. CD150hi Treg cells support HSC quiescence and engraftment via ectoenzyme CD39-generated adenosine. Megakaryocytes control HSC quiescence through TGFβ1 or CXCL4 signaling,.
Figure 3:
Figure 3:. Adaptation of hematopoietic progenitors in cardio-metabolic disease.
IL-1β can act directly on hematopoietic stem and progenitor cells (HSPCs) and is a crucial mediator promoting myelopoiesis under different cardio-metabolic settings like post-myocardial infarction MI, obesity and western-type diet,–. Moreover, in MI, increased sympathoadrenergic activity (e.g., due to pain or anxiety) causes expansion and enhanced egress from the BM of HSPCs, including a subset of CCR2+ HSPCs, further contributing to enhanced myeloid cell output,. This enhanced generation of inflammatory myeloid cells may aggravate inflammation and interfere with tissue healing in the case of MI and perhaps in other inflammatory conditions. GM-CSF produced post-MI (or under other inflammatory disorders) promotes myelopoiesis by acting on HSPCs or myeloid progenitors (MyP),. Cholesterol accumulation in HSPCs (e.g., due to dyslipidemia or hypercholesterolemia) causes membrane changes associated with enhanced IL-3 or GM-CSF-dependent signaling that induces myelopoiesis,. Such immunometabolic changes resulting in GM-CSF-dependent enhanced myelopoiesis are also associated with trained immunity-induced IL-1β and may, at least in part, explain why innate immune training aggravates cardiovascular inflammation.
Figure 4.
Figure 4.. Detrimental feed-forward loop linking HSPC inflammatory adaptation to chronic inflammatory disease.
The ability of HSPCs to sense and adapt to inflammatory stimuli may have detrimental consequences in the setting of chronic inflammatory diseases. According to this hypothesis, the adaptation of HSPCs to inflammatory signals derived from on-going chronic inflammatory disorders (e.g., cardio-metabolic disease) promotes myelopoiesis and output of inflammatory myeloid cells, which in turn further enhance inflammation. This not only can exacerbate the disease but also perpetuate HSPC-mediated myelopoiesis. Thus, a feed-forward loop between inflammation-adapted hematopoietic progenitors and the inflammatory disorder is generated that may contribute to or underlie the chronicity of the disorder.
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