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

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 Payne

Research output: Contribution to journalArticlepeer-review

Abstract

Myelodysplastic syndrome (MDS) is a haematological malignancy characterised by blood cytopenias and predisposition to acute myeloid leukaemia (AML). Therapies for MDS are lacking, particularly those that impact the early stages of disease. We developed a model of MDS using zebrafish using knockout of Rps14,
the primary mediator of the anaemia associated with del (5q) MDS. These mutant animals display dose- and age-dependent abnormalities in haematopoiesis, culminating in bone marrow failure with dysplastic features. We utilized rps14 knockdown to undertake an in vivo small molecule screen to identify compounds that ameliorate the MDS phenotype, identifying imiquimod, an agonist of TLR7 and TLR8. Imiquimod alleviates anaemia by promoting haematopoietic 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 crosstalk between pro-inflammatory pathways endogenous to Rps14 loss and NFkappaB pathway via TLR7. Finally, we show that in highly purified human bone marrow samples from anaemic patients, imiquimod leads to an increase in erythroid output from myelo-erythroid 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 anaemia.
Original languageEnglish
Pages (from-to)4112–4124
JournalBlood Advances
Volume5
Issue number20
Early online date2021
DOIs
Publication statusPublished - 2021
Externally publishedYes

Subject classification (UKÄ)

  • Hematology
  • Cell and Molecular Biology

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