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Endothelial cells translate pathogen signals into G-CSF-driven emergency granulopoiesis


Boettcher, S; Gerosa, R C; Radpour, R; Bauer, J; Ampenberger, F; Heikenwalder, M; Kopf, M; Manz, M G (2014). Endothelial cells translate pathogen signals into G-CSF-driven emergency granulopoiesis. Blood, 124(9):1393-1403.

Abstract

Systemic bacterial infection induces a hematopoietic response program termed "emergency granulopoiesis" that is characterized by increased de novo bone marrow (BM) neutrophil production. How loss of local immune control and bacterial dissemination is sensed and subsequently translated into the switch from steady-state to emergency granulopoiesis is, however, unknown. Using tissue-specific myeloid differentiation primary response gene 88 (Myd88)-deficient mice and in vivo lipopolysaccharide (LPS) administration to model severe bacterial infection, we here show that endothelial cells (ECs) but not hematopoietic cells, hepatocytes, pericytes, or BM stromal cells, are essential cells for this process. Indeed, ECs from multiple tissues including BM express high levels of Tlr4 and Myd88 and are the primary source of granulocyte colony-stimulating factor (G-CSF), the key granulopoietic cytokine, after LPS challenge or infection with Escherichia coli. EC-intrinsic MYD88 signaling and subsequent G-CSF production by ECs is required for myeloid progenitor lineage skewing toward granulocyte-macrophage progenitors, increased colony-forming unit granulocyte activity in BM, and accelerated BM neutrophil generation after LPS stimulation. Thus, ECs catalyze the detection of systemic infection into demand-adapted granulopoiesis.

Abstract

Systemic bacterial infection induces a hematopoietic response program termed "emergency granulopoiesis" that is characterized by increased de novo bone marrow (BM) neutrophil production. How loss of local immune control and bacterial dissemination is sensed and subsequently translated into the switch from steady-state to emergency granulopoiesis is, however, unknown. Using tissue-specific myeloid differentiation primary response gene 88 (Myd88)-deficient mice and in vivo lipopolysaccharide (LPS) administration to model severe bacterial infection, we here show that endothelial cells (ECs) but not hematopoietic cells, hepatocytes, pericytes, or BM stromal cells, are essential cells for this process. Indeed, ECs from multiple tissues including BM express high levels of Tlr4 and Myd88 and are the primary source of granulocyte colony-stimulating factor (G-CSF), the key granulopoietic cytokine, after LPS challenge or infection with Escherichia coli. EC-intrinsic MYD88 signaling and subsequent G-CSF production by ECs is required for myeloid progenitor lineage skewing toward granulocyte-macrophage progenitors, increased colony-forming unit granulocyte activity in BM, and accelerated BM neutrophil generation after LPS stimulation. Thus, ECs catalyze the detection of systemic infection into demand-adapted granulopoiesis.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Hematology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:28 August 2014
Deposited On:05 Feb 2015 16:59
Last Modified:05 Apr 2016 18:48
Publisher:American Society of Hematology
ISSN:0006-4971
Additional Information:This research was originally published in Blood.Blood 2014; 124(9):1393-1403. Copyright by the American Society of Hematology.
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1182/blood-2014-04-570762
PubMed ID:24990886

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