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A late-lineage murine neutrophil precursor population exhibits dynamic changes during demand-adapted granulopoiesis.

ABSTRACT: Homeostasis of neutrophils-the blood cells that respond first to infection and tissue injury-is critical for the regulation of immune responses and regulated through granulopoiesis, a multi-stage process by which neutrophils differentiate from hematopoietic stem cells. Granulopoiesis is a highly dynamic process and altered in certain clinical conditions, such as pathologic and iatrogenic neutropenia, described as demand-adapted granulopoiesis. The regulation of granulopoiesis under stress is not completely understood because studies of granulopoiesis dynamics have been hampered by technical limitations in defining neutrophil precursors. Here, we define a population of neutrophil precursor cells in the bone marrow with unprecedented purity, characterized by the lineage^-CD11b⁺Ly6G^loLy6B^intCD115^-, which we call NeuPs (Neutrophil Precursors). We demonstrated that NeuPs differentiate into mature and functional neutrophils both in vitro and in vivo. By analyzing the gene expression profiles of NeuPs, we also identified NeuP stage-specific genes and characterized patterns of gene regulation throughout granulopoiesis. Importantly, we found that NeuPs have the potential to proliferate, but the proliferation decreased in multiple different hematopoietic stress settings, indicating that proliferating NeuPs are poised at a critical step to regulate granulopoiesis. Our findings will facilitate understanding how the hematopoietic system maintains homeostasis and copes with the demands of granulopoiesis.

SUBMITTER: Kim MH

PROVIDER: S-EPMC5216372 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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A late-lineage murine neutrophil precursor population exhibits dynamic changes during demand-adapted granulopoiesis.

Kim Min-Hyeok MH Yang Dongchan D Kim Mirang M Kim Seon-Young SY Kim Dongsup D Kang Suk-Jo SJ

Scientific reports 20170106

Homeostasis of neutrophils-the blood cells that respond first to infection and tissue injury-is critical for the regulation of immune responses and regulated through granulopoiesis, a multi-stage process by which neutrophils differentiate from hematopoietic stem cells. Granulopoiesis is a highly dynamic process and altered in certain clinical conditions, such as pathologic and iatrogenic neutropenia, described as demand-adapted granulopoiesis. The regulation of granulopoiesis under stress is not ...[more]

PMID: 28059162

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Project description:BackgroundMyocardial infarction (MI) triggers myelopoiesis, resulting in heightened production of neutrophils. However, the mechanisms that sustain their production and recruitment to the injured heart are unclear.MethodsUsing a mouse model of the permanent ligation of the left anterior descending artery and flow cytometry, we first characterized the temporal and spatial effects of MI on different myeloid cell types. We next performed global transcriptome analysis of different cardiac cell types within the infarct to identify the drivers of the acute inflammatory response and the underlying signaling pathways. Using a combination of genetic and pharmacological strategies, we identified the sequelae of events that led to MI-induced myelopoiesis. Cardiac function was assessed by echocardiography. The association of early indexes of neutrophilia with major adverse cardiovascular events was studied in a cohort of patients with acute MI.ResultsInduction of MI results in rapid recruitment of neutrophils to the infarct, where they release specific alarmins, S100A8 and S100A9. These alarmins bind to the Toll-like receptor 4 and prime the nod-like receptor family pyrin domain-containing 3 inflammasome in naïve neutrophils and promote interleukin-1β secretion. The released interleukin-1β interacts with its receptor (interleukin 1 receptor type 1) on hematopoietic stem and progenitor cells in the bone marrow and stimulates granulopoiesis in a cell-autonomous manner. Genetic or pharmacological strategies aimed at disruption of S100A8/A9 and their downstream signaling cascade suppress MI-induced granulopoiesis and improve cardiac function. Furthermore, in patients with acute coronary syndrome, higher neutrophil count on admission and after revascularization correlates positively with major adverse cardiovascular disease outcomes.ConclusionsOur study provides novel evidence for the primary role of neutrophil-derived alarmins (S100A8/A9) in dictating the nature of the ensuing inflammatory response after myocardial injury. Therapeutic strategies aimed at disruption of S100A8/A9 signaling or their downstream mediators (eg, nod-like receptor family pyrin domain-containing 3 inflammasome, interleukin-1β) in neutrophils suppress granulopoiesis and may improve cardiac function in patients with acute coronary syndrome.

Dataset Information

A late-lineage murine neutrophil precursor population exhibits dynamic changes during demand-adapted granulopoiesis.

Publications

A late-lineage murine neutrophil precursor population exhibits dynamic changes during demand-adapted granulopoiesis.

Similar Datasets

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