Blood Journal
Leading the way in experimental and clinical research in hematology

Steady-state neutrophil homeostasis is dependent on TLR4/TRIF signaling

  1. Stefanie Bugl1,*,
  2. Stefan Wirths1,*,
  3. Markus P. Radsak2,
  4. Hansjörg Schild3,
  5. Pamela Stein3,
  6. Maya C. André4,
  7. Martin R. Müller1,
  8. Elke Malenke1,
  9. Tina Wiesner1,
  10. Melanie Märklin1,
  11. Julia-Stefanie Frick5,
  12. Rupert Handgretinger3,
  13. Hans-Georg Rammensee6,
  14. Lothar Kanz1, and
  15. Hans-Georg Kopp1
  1. 1Department of Medical Oncology, Hematology, Immunology, Rheumatology and Pulmonology, Medical Center II, South West German Comprehensive Cancer Center, University Hospital of Tuebingen, Tuebingen, Germany;
  2. 2Department of Internal Medicine III (Hematology, Oncology, Pneumology), Johannes Gutenberg University Medical Center, Mainz, Germany;
  3. 3Institute for Immunology, Johannes Gutenberg University Medical Center, Mainz, Germany;
  4. 4Department of Pediatric Hematology and Oncology, University Children's Hospital, Tuebingen, Germany;
  5. 5Institute of Medical Microbiology and Hygiene, Eberhard Karls University Tuebingen, Tuebingen, Germany; and
  6. 6Department of Immunology, Institute for Cell Biology, Eberhard Karls University Tuebingen, Tuebingen, Germany

Key Points

  • Steady-state and emergency granulopoiesis are both dependent on TLR signaling.

Abstract

Polymorphonuclear neutrophil granulocytes (neutrophils) are tightly controlled by an incompletely understood homeostatic feedback loop adjusting the marrow's supply to peripheral needs. Although it has long been known that marrow cellularity is inversely correlated with G-CSF levels, the mechanism linking peripheral clearance to production remains unknown. Herein, the feedback response to antibody induced neutropenia is characterized to consist of G-CSF–dependent shifts of marrow hematopoietic progenitor populations including expansion of the lin/Sca-1+/c-kit+ (LSK) and granulocyte macrophage progenitor (GMP) compartments at the expense of thrombopoietic and red cell precursors. Evidence is provided that positive feedback regulation is independent from commensal germs as well as T, B, and NK cells. However, in vivo feedback is impaired in TLR4−/− and TRIF−/−, but not MyD88−/− animals. In conclusion, steady-state neutrophil homeostasis is G-CSF–dependent and regulated through pattern-recognition receptors, thereby directly linking TLR-triggering to granulopoiesis.

  • Submitted May 18, 2012.
  • Accepted November 13, 2012.
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