Header

UZH-Logo

Maintenance Infos

Pathogen-induced TLR4-TRIF innate immune signaling in hematopoietic stem cells promotes proliferation but reduces competitive fitness


Takizawa, Hitoshi; Fritsch, Kristin; Kovtonyuk, Larisa V; Saito, Yasuyuki; Yakkala, Chakradhar; Jacobs, Kurt; Ahuja, Akshay K; Lopes, Massimo; Hausmann, Annika; Hardt, Wolf-Dietrich; Gomariz, Álvaro; Nombela-Arrieta, César; Manz, Markus G (2017). Pathogen-induced TLR4-TRIF innate immune signaling in hematopoietic stem cells promotes proliferation but reduces competitive fitness. Cell Stem Cell, 21(2):225-240.e5.

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.

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.

Statistics

Citations

2 citations in Web of Science®
1 citation in Scopus®
Google Scholar™

Altmetrics

Downloads

1 download since deposited on 29 Aug 2017
1 download since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Hematology
04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:3 August 2017
Deposited On:29 Aug 2017 13:19
Last Modified:09 Dec 2017 01:59
Publisher:Cell Press (Elsevier)
ISSN:1875-9777
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.stem.2017.06.013
PubMed ID:28736216

Download