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

• Published in: Blood advances Vol. 5; no. 20; pp. 4112 - 4124
• Main Authors: Peña, Oscar A., Lubin, Alexandra, Hockings, Catherine, Rowell, Jasmine, Jung, Youngrock, Hoade, Yvette, Dace, Phoebe, Valdivia, Leonardo E., Tuschl, Karin, Böiers, Charlotta, Virgilio, Maria C., Richardson, Simon, Payne, Elspeth M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.10.2021; American Society of Hematology
• Subjects: Animals; Hematopoiesis; Hematopoiesis and Stem Cells; Humans; Myelodysplastic Syndromes - genetics; Signal Transduction; Toll-Like Receptor 7 - genetics; Zebrafish
• ISSN: 2473-9529; 2473-9537
• DOI: 10.1182/bloodadvances.2020003055

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-κB 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. •Rps14-deficient zebrafish demonstrate features of MDS and impaired stress responses.•Rps14-induced anemia is rescued on ligation of Tlr7, via paradoxical suppression of inflammatory signalling and enhanced differentiation. [Display omitted]