Systemic TLR2 agonist exposure regulates hematopoietic stem cells via cell-autonomous and cell-non-autonomous mechanisms.
Toll-like receptor 2 (TLR2) is a member of the TLR family of receptors that play a central role in innate immunity. In addition to regulating effector immune cells, where it recognizes a wide variety of pathogen-associated and nonpathogen-associated endogenous ligands, TLR2 is expressed in hematopoietic stem cells (HSCs). Its role in HSCs, however, is not well understood. Furthermore, augmented TLR2 signaling is associated with myelodysplastic syndrome, an HSC disorder characterized by ineffective hematopoiesis and a high risk of transformation to leukemia, suggesting that aberrant signaling through this receptor may have clinically significant effects on HSCs. Herein, we show that systemic exposure of mice to a TLR2 agonist leads to an expansion of bone marrow and spleen phenotypic HSCs and progenitors, but a loss of HSC self-renewal capacity. Treatment of chimeric animals shows that these effects are largely cell non-autonomous, with a minor contribution from cell-autonomous TLR2 signaling, and are in part mediated by granulocyte colony-stimulating factor and tumor necrosis factor-α. Together, these data suggest that TLR2 ligand exposure influences HSC cycling and function via unique mechanisms from TLR4, and support an important role for TLR2 in the regulation of HSCs.
Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA.
A C
AC
Herman
Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA.
D A
DA
Monlish
Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA.
M P
MP
Romine
Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA.
S T
ST
Bhatt
Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA.
S
S
Zippel
Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA.
L G
LG
Schuettpelz
D000818:Animals; D015415:Biomarkers; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016026:Bone Marrow Transplantation; D003114:Colony-Forming Units Assay; D016207:Cytokines / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D011836:Radiation Tolerance / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D013154:Spleen / Q000166:cytology; D051195:Toll-Like Receptor 2 / Q000819:agonists*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology
D015415:Biomarkers; D016207:Cytokines; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor