Systemic TLR2 Agonist Exposure Regulates Hematopoietic Stem Cells Via Cell-autonomous and Cell-non-autonomous Mechanisms

Overview

Journal Blood Cancer J

Date 2016 Jun 18

PMID 27315114

Citations 35

Authors

A C Herman

D A Monlish

M P Romine

S T Bhatt

S Zippel

L G Schuettpelz

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Hematopoietic stem cell a reservoir of innate immune memory.

Ruffinatto L, Groult Y, Iacono J, Sarrazin S, de Laval B Front Immunol. 2024; 15:1491729.

PMID: 39720722 PMC: 11666435. DOI: 10.3389/fimmu.2024.1491729.

Blood and guts: how the intestinal microbiome shapes hematopoiesis and treatment of hematologic disease.

Fernandez Sanchez J, Maknojia A, King K Blood. 2024; 143(17):1689-1701.

PMID: 38364184 PMC: 11103099. DOI: 10.1182/blood.2023021174.

The TLR2/TLR6 ligand FSL-1 mitigates radiation-induced hematopoietic injury in mice and nonhuman primates.

Brickey W, Caudell D, Macintyre A, Olson J, Dai Y, Li S Proc Natl Acad Sci U S A. 2023; 120(50):e2122178120.

PMID: 38051771 PMC: 10723152. DOI: 10.1073/pnas.2122178120.

Hematopoietic stem cells undergo a lymphoid to myeloid switch in early stages of emergency granulopoiesis.

Vanickova K, Milosevic M, Ribeiro Bas I, Burocziova M, Yokota A, Danek P EMBO J. 2023; 42(23):e113527.

PMID: 37846891 PMC: 10690458. DOI: 10.15252/embj.2023113527.

Systemic administration of STING agonist promotes myeloid cells maturation and antitumor immunity through regulating hematopoietic stem and progenitor cell fate.

Xu T, Dai J, Tang L, Sun L, Si L, Guo J Cancer Immunol Immunother. 2023; 72(11):3491-3505.

PMID: 37550427 PMC: 10991199. DOI: 10.1007/s00262-023-03502-7.

References

De Luca K, Frances-Duvert V, Asensio M, Ihsani R, Debien E, Taillardet M . The TLR1/2 agonist PAM(3)CSK(4) instructs commitment of human hematopoietic stem cells to a myeloid cell fate. Leukemia. 2009; 23(11):2063-74. DOI: 10.1038/leu.2009.155. View

Joo Y, Lee W, Won H, Lee S, Choi J, Lee S . Upregulation of TLR2 expression on G-CSF-mobilized peripheral blood stem cells is responsible for their rapid engraftment after allogeneic hematopoietic stem cell transplantation. Cytokine. 2011; 54(1):36-42. DOI: 10.1016/j.cyto.2010.12.020. View

Zhao J, Ma C, OConnell R, Mehta A, DiLoreto R, Heath J . Conversion of danger signals into cytokine signals by hematopoietic stem and progenitor cells for regulation of stress-induced hematopoiesis. Cell Stem Cell. 2014; 14(4):445-459. PMC: 4119790. DOI: 10.1016/j.stem.2014.01.007. View

Granick J, Falahee P, Dahmubed D, Borjesson D, Miller L, Simon S . Staphylococcus aureus recognition by hematopoietic stem and progenitor cells via TLR2/MyD88/PGE2 stimulates granulopoiesis in wounds. Blood. 2013; 122(10):1770-8. PMC: 3765058. DOI: 10.1182/blood-2012-11-466268. View

Harrison D, Jordan C, Zhong R, Astle C . Primitive hemopoietic stem cells: direct assay of most productive populations by competitive repopulation with simple binomial, correlation and covariance calculations. Exp Hematol. 1993; 21(2):206-19. View

Starczynowski D, Kuchenbauer F, Argiropoulos B, Sung S, Morin R, Muranyi A . Identification of miR-145 and miR-146a as mediators of the 5q- syndrome phenotype. Nat Med. 2009; 16(1):49-58. DOI: 10.1038/nm.2054. View

Ichii M, Shimazu T, Welner R, Garrett K, Zhang Q, Esplin B . Functional diversity of stem and progenitor cells with B-lymphopoietic potential. Immunol Rev. 2010; 237(1):10-21. PMC: 2928143. DOI: 10.1111/j.1600-065X.2010.00933.x. View

Dimicoli S, Wei Y, Bueso-Ramos C, Yang H, DiNardo C, Jia Y . Overexpression of the toll-like receptor (TLR) signaling adaptor MYD88, but lack of genetic mutation, in myelodysplastic syndromes. PLoS One. 2013; 8(8):e71120. PMC: 3744562. DOI: 10.1371/journal.pone.0071120. View

Pronk C, Veiby O, Bryder D, Jacobsen S . Tumor necrosis factor restricts hematopoietic stem cell activity in mice: involvement of two distinct receptors. J Exp Med. 2011; 208(8):1563-70. PMC: 3149225. DOI: 10.1084/jem.20110752. View

10.

Megias J, Yanez A, Moriano S, OConnor J, Gozalbo D, Gil M . Direct Toll-like receptor-mediated stimulation of hematopoietic stem and progenitor cells occurs in vivo and promotes differentiation toward macrophages. Stem Cells. 2012; 30(7):1486-95. DOI: 10.1002/stem.1110. View

11.

Rodriguez S, Chora A, Goumnerov B, Mumaw C, Goebel W, Fernandez L . Dysfunctional expansion of hematopoietic stem cells and block of myeloid differentiation in lethal sepsis. Blood. 2009; 114(19):4064-76. PMC: 2774548. DOI: 10.1182/blood-2009-04-214916. View

12.

Maratheftis C, Andreakos E, Moutsopoulos H, Voulgarelis M . Toll-like receptor-4 is up-regulated in hematopoietic progenitor cells and contributes to increased apoptosis in myelodysplastic syndromes. Clin Cancer Res. 2007; 13(4):1154-60. DOI: 10.1158/1078-0432.CCR-06-2108. View

13.

Esplin B, Shimazu T, Welner R, Garrett K, Nie L, Zhang Q . Chronic exposure to a TLR ligand injures hematopoietic stem cells. J Immunol. 2011; 186(9):5367-75. PMC: 3086167. DOI: 10.4049/jimmunol.1003438. View

14.

Schuettpelz L, Borgerding J, Christopher M, Gopalan P, Romine M, Herman A . G-CSF regulates hematopoietic stem cell activity, in part, through activation of Toll-like receptor signaling. Leukemia. 2014; 28(9):1851-60. PMC: 4130805. DOI: 10.1038/leu.2014.68. View

15.

Farhat K, Riekenberg S, Heine H, Debarry J, Lang R, Mages J . Heterodimerization of TLR2 with TLR1 or TLR6 expands the ligand spectrum but does not lead to differential signaling. J Leukoc Biol. 2007; 83(3):692-701. DOI: 10.1189/jlb.0807586. View

16.

de Bruin A, Voermans C, Nolte M . Impact of interferon-γ on hematopoiesis. Blood. 2014; 124(16):2479-86. DOI: 10.1182/blood-2014-04-568451. View

17.

Burberry A, Zeng M, Ding L, Wicks I, Inohara N, Morrison S . Infection mobilizes hematopoietic stem cells through cooperative NOD-like receptor and Toll-like receptor signaling. Cell Host Microbe. 2014; 15(6):779-91. PMC: 4085166. DOI: 10.1016/j.chom.2014.05.004. View

18.

Wei Y, Dimicoli S, Bueso-Ramos C, Chen R, Yang H, Neuberg D . Toll-like receptor alterations in myelodysplastic syndrome. Leukemia. 2013; 27(9):1832-40. PMC: 4011663. DOI: 10.1038/leu.2013.180. View

19.

Nagai Y, Garrett K, Ohta S, Bahrun U, Kouro T, Akira S . Toll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment. Immunity. 2006; 24(6):801-812. PMC: 1626529. DOI: 10.1016/j.immuni.2006.04.008. View

20.

Rebel V, Hartnett S, Hill G, Lazo-Kallanian S, Ferrara J, Sieff C . Essential role for the p55 tumor necrosis factor receptor in regulating hematopoiesis at a stem cell level. J Exp Med. 1999; 190(10):1493-504. PMC: 2195701. DOI: 10.1084/jem.190.10.1493. View