Steffen Boettcher

Demand-adapted regulation of early hematopoiesis in infection and inflammation.

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.

Cutting Edge: LPS-Induced Emergency Myelopoiesis Depends on TLR4-Expressing Nonhematopoietic Cells

Systemic bacterial infection is rapidly recognized as an emergency state leading to neutrophil release into the circulation and increased myeloid cell production within the bone marrow. However, the mechanisms of sensing infection and subsequent translation into emergency myelopoiesis have not been defined. In this study, we demonstrate in vivo in mice that, surprisingly, selective TLR4 expression within the hematopoietic compartment fails to induce LPS-driven emergency myelopoiesis. In contrast, TLR4-expressing nonhematopoietic cells are indispensable for LPS-induced, G-CSF–mediated myelopoietic responses. Furthermore, LPS-induced emergency myelopoiesis is independent of intact IL-1RI signaling and, thus, does not require inflammasome activation. Collectively, our findings reveal a key and nonredundant role for nonhematopoietic compartment pathogen sensing that is subsequently translated into cytokine release for enhanced, demand-adapted myeloid cell production.

A novel mouse model for inhibition of DOHH-mediated hypusine modification reveals a crucial function in embryonic development, proliferation and oncogenic transformation

The central importance of translational control by post-translational modification has spurred major interest in regulatory pathways that control translation. One such pathway uniquely adds hypusine to eukaryotic initiation factor 5A (eIF5A), and thereby affects protein synthesis and, subsequently, cellular proliferation through an unknown mechanism. Using a novel conditional knockout mouse model and a Caenorhabditis elegans knockout model, we found an evolutionarily conserved role for the DOHH-mediated second step of hypusine synthesis in early embryonic development. At the cellular level, we observed reduced proliferation and induction of senescence in 3T3 Dohh−/− cells as well as reduced capability for malignant transformation. Furthermore, mass spectrometry showed that deletion of DOHH results in an unexpected complete loss of hypusine modification. Our results provide new biological insight into the physiological roles of the second step of the hypusination of eIF5A. Moreover, the conditional mouse model presented here provides a powerful tool for manipulating hypusine modification in a temporal and spatial manner, to analyse both how this unique modification normally functions in vivo as well as how it contributes to different pathological conditions.

Regulation of Inflammation- and Infection-Driven Hematopoiesis

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.

Sensing and translation of pathogen signals into demand-adapted myelopoiesis.

Purpose of reviewDuring severe systemic infection, steady-state hematopoiesis is switched to demand-adapted myelopoiesis, leading to increased myeloid progenitor proliferation and, depending on the context and type of pathogen, enhanced granulocytic or monocytic differentiation, respectively. We will review the recent advances in understanding direct and indirect mechanisms by which different pathogen signals are detected and subsequently translated into demand-adapted myelopoiesis. Recent findingsEnhanced myeloid progenitor proliferation and neutrophil differentiation following infection with prototypic Gram-negative bacterium Escherichia coli is mediated by granulocyte colony-stimulating factor, and reactive oxygen species released from endothelial cells and mature myeloid cells, respectively. Furthermore, hematopoietic stem and progenitor cells directly sense pathogen signals via Toll-like receptors and contribute to emergency granulopoiesis via release and subsequent autocrine and paracrine action of myelopoietic cytokines including IL-6. Moreover, emergency monocytopoiesis upon viral infection depends on T cell-derived IFN&ggr; and release of IL-6 from bone marrow stromal cells. SummaryA complex picture is evolving in which various hematopoietic and nonhematopoietic cell types interact with the hematopoietic system in an intricate manner to shape an appropriate hematopoietic response to specific infectious stimuli.

LPS-stimulated human bone marrow stroma cells support myeloid cell development and progenitor cell maintenance

The nonhematopoietic bone marrow (BM) microenvironment provides a functional niche for hematopoietic cell maintenance, recruitment, and differentiation. It consists of multiple cell types including vasculature, bone, adipose tissue, and fibroblast-like bone marrow stromal cells (BMSC), which can be summarized under the generic term niche cells. BMSC express Toll-like receptors (TLRs) and are capable to respond to TLR-agonists by changing their cytokine expression pattern in order to more efficiently support hematopoiesis. Here, we show that in addition to enhanced myeloid colony formation from human CD34+ cells, lipopolysaccharide (LPS) stimulation retains overall higher numbers of CD34+ cells in co-culture assays using BMSC, with eightfold more CD34+ cells that underwent up to three divisions as compared to non-stimulated assays. When subjected to cytokine-supplemented myeloid colony-forming unit (CFU) assays or transplanted into newborn RAG2−/− γc−/− mice, CD34+ cells from LPS-stimulated BMSC cultures give rise to the full spectrum of myeloid colonies and T and B cells, respectively, thus supporting maintenance of myeloid and lymphoid primed hematopoietic progenitor cells (HPCs) under inflammatory conditions. Collectively, we suggest that BMSC enhance hematopoiesis during inflammatory conditions to support the replenishment of innate immune effector cells and to prevent the exhaustion of the hematopoietic stem and progenitor cell (HSPC) pool.