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Cell Stem Cell. 2017 Aug 3;21(2):225-240.e5. doi: 10.1016/j.stem.2017.06.013. Epub 2017 Jul 20.

Pathogen-Induced TLR4-TRIF Innate Immune Signaling in Hematopoietic Stem Cells Promotes Proliferation but Reduces Competitive Fitness.

Author information

1
Hematology, University Hospital Zurich and University of Zurich, 8091 Zurich, Switzerland; International Research Center for Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan. Electronic address: htakizawa@kumamoto-u.ac.jp.
2
Hematology, University Hospital Zurich and University of Zurich, 8091 Zurich, Switzerland.
3
Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland.
4
Institute of Microbiology, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland.
5
Hematology, University Hospital Zurich and University of Zurich, 8091 Zurich, Switzerland. Electronic address: markus.manz@usz.ch.

Abstract

Bacterial infection leads to consumption of short-lived innate immune effector cells, which then need to be replenished from hematopoietic stem and progenitor cells (HSPCs). HSPCs express pattern recognition receptors, such as Toll-like receptors (TLRs), and ligation of these receptors induces HSPC mobilization, cytokine production, and myeloid differentiation. The underlying mechanisms involved in pathogen signal transduction in HSCs and the resulting biological consequences remain poorly defined. Here, we show that in vivo lipopolysaccharide (LPS) application induces proliferation of dormant HSCs directly via TLR4 and that sustained LPS exposure impairs HSC self-renewal and competitive repopulation activity. This process is mediated via TLR4-TRIF-ROS-p38, but not MyD88 signaling, and can be inhibited pharmacologically without preventing emergency granulopoiesis. Live Salmonella Typhimurium infection similarly induces proliferative stress in HSCs, in part via TLR4-TRIF signals. Thus, while direct TLR4 activation in HSCs might be beneficial for controlling systemic infection, prolonged TLR4 signaling has detrimental effects and may contribute to inflammation-associated HSPC dysfunction.

KEYWORDS:

Toll-like receptor 4; competitive fitness; gram-negative bacteria; hematopoietic stem cell; proliferative stress

PMID:
28736216
DOI:
10.1016/j.stem.2017.06.013
[Indexed for MEDLINE]
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