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

  • Boettcher S
  • Gerosa R
  • Radpour R
 et al. 
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Abstract

Key Points • ECs express Tlr4 and Myd88 and, after in vivo LPS or E coli stimulation, are the prime sources of G-CSF. • ECs are sensors of systemically spread pathogens and subsequent drivers of BM emergency granulopoiesis. Systemic bacterial infection induces a hematopoietic response program termed " emer-gency 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 essen-tial 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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Authors

  • Steffen Boettcher

  • Rahel C. Gerosa

  • Ramin Radpour

  • Judith Bauer

  • Franziska Ampenberger

  • Mathias Heikenwalder

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