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

Stefanie Bugl, Stefan Wirths, Markus P. Radsak, Hansjörg Schild, Pamela Stein, Maya C. André, Martin R. Müller, Elke Malenke, Tina Wiesner, Melanie Märklin, Julia-Stefanie Frick, Rupert Handgretinger, Hans-Georg Rammensee, Lothar Kanz, Hans-Georg Kopp

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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