Emerging Principles in Myelopoiesis at Homeostasis and during Infection and Inflammation

Abstract

Myelopoiesis ensures the steady state of the myeloid cell compartment. Technological advances in fate mapping and genetic engineering, as well as the advent of single cell RNA-sequencing, have highlighted the heterogeneity of the hematopoietic system and revealed new concepts in myeloid cell ontogeny. These technologies are also shedding light on mechanisms of myelopoiesis at homeostasis and at different phases of infection and inflammation, illustrating important feedback loops between affected tissues and the bone marrow. We review these findings here and revisit principles in myelopoiesis in light of the evolving understanding of myeloid cell ontogeny and heterogeneity. We argue for the importance of system-wide evaluation of changes in myelopoiesis and discuss how even after the resolution of inflammation, long-lasting alterations in myelopoiesis may play a role in innate immune memory or trained immunity.

Severe COVID-19 Is Marked by a Dysregulated Myeloid Cell Compartment

“…Differential gene expression analysis for each cluster revealed extensive phenotypic heterogeneity within the LDN compartment ( Figure 5 B). LDNs mainly arise under pathological conditions, such as severe infection and sepsis in the context of emergency myelopoiesis ( Schultze et al., 2019 ), and they have been associated with dysfunctional immune responses, marked by combined immunosuppression and inflammation ( Silvestre-Roig et al., 2019 ). While LDN in cluster 1 expressed numerous ISGs ( ISG15 , IFITM1/3 , and RSAD2 ), cluster 4 (pro-neutrophils) expressed genes (e.g., MPO , ELANE , and PRTN3 ) that are involved in neutrophil extracellular trap formation ( Stiel et al., 2018 ; Thomas et al., 2014 ; You et al., 2019 ) among other functions and that have been associated with sepsis ( Ahmad et al., 2019 ; Carbon et al., 2019 ; Silvestre-Roig et al., 2019 ).…”

A rule-based data-informed cellular consensus map of the human mononuclear phagocyte cell space

“…It is therefore of utmost importance to establish a precise baseline during 25 homeostasis as provided here by our new consensus map, to allow for a better understanding of any deviations of the myeloid cell compartment during stress, pathophysiological conditions and diseases. Furthermore, the dynamic processes of myelopoiesis during homeostasis but even more so during inflammatory conditions requires precise mapping of cellular identities as a prerequisite to identify targets for precise therapeutic intervention (Dick et al, 2019;Schultze, 2019;Schultze et al, 2019). Furthermore, the necessity to continuously iterate the process of 5 improving the consensus maps is nicely illustrated by the accompanying manuscript by Dutertre et al (Dutertre et al, 2019), further defining the cellular relationship of DC2/3 and monocytes.…”

Interplay of Heme with Macrophages in Homeostasis and Inflammation

“…An important role in this regulatory pathway has been ascribed to the mutual interaction of BACH1 and 2 with the pro-inflammatory TF C/EBPbeta at the activating protein-1 (AP-1) binding site within the BACH recognition element [82]. Notably, BACH1 and 2-dependent modulation of hematopoiesis at the erythro-myeloid bifurcation may not only be important in the pathogenesis of AI, but also in that of the myelodysplastic syndrome [83,84]. The detailed role of heme in these complex regulatory pathways of HSPCs remains to be established.…”