TLR7 ligation augments hematopoiesis in Rps14 (uS11) deficiency via paradoxical suppression of inflammatory signaling

Oscar A. Peña, Alexandra Lubin, Catherine Hockings, Jasmine Rowell, Youngrock Jung, Yvette Hoade, Phoebe Dace, Leonardo E. Valdivia, Karin Tuschl, Charlotta Böiers, Maria C. Virgilio, Simon Richardson, Elspeth M. Payne*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

5 Citations (Scopus)
44 Downloads (Pure)

Abstract

Myelodysplastic syndrome (MDS) is a hematological malignancy characterized by blood cytopenias and predisposition to acute myeloid leukemia (AML). Therapies for MDS are lacking, particularly those that have an impact in the early stages of disease. We developed a model of MDS in zebrafish with knockout of Rps14, the primary mediator of the anemia associated with del(5q) MDS. These mutant animals display dose- and age-dependent abnormalities in hematopoiesis, culminating in bone marrow failure with dysplastic features. We used Rps14 knockdown to undertake an in vivo small-molecule screening, to identify compounds that ameliorate the MDS phenotype, and we identified imiquimod, an agonist of Toll-like receptor-7 (TLR7) and TLR8. Imiquimod alleviates anemia by promoting hematopoietic stem and progenitor cell expansion and erythroid differentiation, the mechanism of which is dependent on TLR7 ligation and Myd88. TLR7 activation in this setting paradoxically promoted an anti-inflammatory gene signature, indicating cross talk via TLR7 between proinflammatory pathways endogenous to Rps14 loss and the NF-kB pathway. Finally, in highly purified human bone marrow samples from anemic patients, imiquimod led to an increase in erythroid output from myeloerythroid progenitors and common myeloid progenitors. Our findings have both specific implications for the development of targeted therapeutics for del(5q) MDS and wider significance identifying a potential role for TLR7 ligation in modifying anemia.

Original languageEnglish
Pages (from-to)4112-4124
Number of pages13
JournalBlood Advances
Volume5
Issue number20
DOIs
Publication statusPublished - 26 Oct 2021

Bibliographical note

Funding Information:
E.M.P. was supported by a CRUK Advanced Clinician Scientist Fellowship and is a former recipient of a Wellcome-Beit Intermediate Clinical Fellowship and the Leuka John Goldman

Funding Information:
E.M.P. was supported by a CRUK Advanced Clinician Scientist Fellowship and is a former recipient of a Wellcome-Beit Intermediate Clinical Fellowship and the Leuka John Goldman Fellowship for future science. C.H. was supported by a Medical Research Council Clinical Research Training Fellowship. O.P. was supported by BECAS Chile (CONICYT) and Overseas Research Scholarship (UCL). L.E.V. was supported by a FONDECYT grant (11160951) and Medical Research Council grants G0900994 and MR/L003775/1 (Steve W. Wilson and Gaia Gestri, Department of Cell and Developmental Biology, UCL). C.B. was supported by the Swedish Research Council (grant 2015-00135) and Marie Sklodowskan Curie Actions, Cofund, and Project INCA (grant 600398).

Publisher Copyright:
© 2021 by The American Society of Hematology.

Fingerprint

Dive into the research topics of 'TLR7 ligation augments hematopoiesis in Rps14 (uS11) deficiency via paradoxical suppression of inflammatory signaling'. Together they form a unique fingerprint.

Cite this