Neutrophil homeostasis and its regulation by danger signaling

Abstract

Hematopoiesis in general is demand driven and adaptive, but in contrast to erythropoiesis or thrombocytopoiesis, our knowledge on how neutrophil production is adapted to individual needs remains incomplete. Recently, neutrophil homeostasis has been shown to depend on danger receptors, macrophages, and even circadian rhythms. Puzzle pieces for a broader view of neutrophil homeostasis accumulate, and we will herein try to put seemingly contradictory evidence in a perspective of neutrophil homeostasis and emergency granulopoiesis determined by innate immunologic signaling.

Microbial messaging to the marrow

“…1 Granulopoiesis appears to be controlled by distinct mechanisms in homeostatic and demand conditions, including reliance on G-CSF and transcriptional regulators in the CCAAT enhancer-binding family. 2,3,8 Steadystate neutrophil production is largely but not entirely dependent on G-CSF, whereas demand-driven granulopoiesis can proceed in at least some conditions without this cytokine. 9 Endothelial MyD88 deficiency does not suppress basal neutrophil amounts, indicating that other cellular sources and mechanisms control steady-state G-CSF amounts and neutrophil development.…”

“…High-resolution genetic profiling of ALL reveals an increasing number of underlying mutations that modify the function of transcription factors, epigenetic regulators, or components of signaling pathways, among others. 2 For decades, cytogeneticists have been aware of specific chromosomal translocations, some of which have been established as reliable risk factors (see figure). However, these genetic risk factors identify only some of the patients at risk.…”

“…The most common submicroscopic genetic lesions include CNAs or sequence mutations of hematopoietic transcription factors, including PAX5, IKZF1, and EBF1; gene rearrangements leading to overexpression of the cytokine receptor component CRLF2; mutations in JAK1 and JAK2 kinases; and deletions of the CDKN2A/B loci encoding the INK4/ARF tumor suppressor genes, to name representative examples. 2 Several of these lesions have been associated with less favorable outcome (such as CDKN2A/ CDKN2B and IKFZ1 deletions 5,6 and…”

“…A severe reduction in numbers predisposes to life-threatening infection and, consistently, numerous mechanisms regulate neutrophil homeostasis. 2 Emergency granulopoiesis describes a rapid physiological response in which circulating neutrophil amounts become significantly elevated. 3 This occurs during bacterial or fungal infection and is important for effective microbial clearance.…”

“…9 Endothelial MyD88 deficiency does not suppress basal neutrophil amounts, indicating that other cellular sources and mechanisms control steady-state G-CSF amounts and neutrophil development. 2 Although G-CSF administration can compensate for endothelial MyD88 deficiency by eliciting emergency granulopoiesis upon LPS challenge, 1 it remains possible that systemic LPS delivery and bacterial infection induce production of additional granulopoietic cytokines (eg, interleukin-6, granulocyte-macrophage colony-stimulating factor), which contribute to the emergency response. In fact, emergency granulopoiesis was not affected as severely in mice lacking endothelial MyD88 after E coli infection compared with systemic LPS treatment, 1 suggesting E coli stimulates multiple danger recognition pathways and additional downstream mediators that ensure induction of a robust hematopoietic response.…”