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TLR7 ligation augments hematopoiesis in Rps14 deficiency via paradoxical inflammatory signalling

ABSTRACT: TLR7 ligation augments hematopoiesis in Rps14 deficiency via paradoxical inflammatory signalling

PROVIDER: PRJNA713782 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13938338_1.fastq.gz	Fastqsanger.gz
	SRR13938338_2.fastq.gz	Fastqsanger.gz
	SRR13938339_1.fastq.gz	Fastqsanger.gz
	SRR13938339_2.fastq.gz	Fastqsanger.gz
	SRR13938340_1.fastq.gz	Fastqsanger.gz

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TLR7 ligation augments hematopoiesis in Rps14 deficiency via paradoxical inflammatory signalling

Project description:Myelodysplastic syndrome (MDS) is a haematological malignancy characterised by blood cytopenias and predisposition to acute myeloid leukaemia. 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 develop bone marrow failure with dysplastic features. We conducted an in vivo small molecule screen to identify compounds that ameliorate the MDS phenotype, identifying imiquimod, an agonist of TLR7. We conducted RNA-seq analysis of both treated and untreated animals to define the mechanism of imiquimod in alleviating anaemia. We find imiquimod alleviates anaemia by promoting haematopoietic stem and progenitor cell expansion and erythroid differentiation, the mechanism of which is dependent on TLR7 ligation. TLR7 activation in this setting paradoxically promoted an anti-inflammatory gene signature suggesting crosstalk between pro-inflammatory pathways endogenous to Rps14 loss and TLR7 pathway activation.

2021-03-12 | GSE168727 | GEO

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

Project description: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.

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shRNA profiling of human cells infected with control or RPS14 shRNAs

Project description:We performed genome-wide expression profiling of cells infected with control or RPS14 shRNAs. Experiment Overall Design: The purpose of the dataset is to profile analyze the effect of silencing RPS14

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TLR7 gene duplication accelerates autoimmunity and promotes nucleolar-specific B cells

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Project description:We performed genome-wide expression profiling of cells infected with control or RPS14 shRNAs. Keywords: controls vs. shRNA treated

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TLR7 gene duplication accelerates autoimmunity and promotes nucleolar-specific B cells

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mRNA length and 3’UTR structure govern the translation selectivity in RPS14-haploinsufficient erythroblasts

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UNC93B1 variants underlie TLR7-dependent autoimmunity

Project description:UNC93B1 is critical for trafficking and function of nucleic acid-sensing Toll-like receptors (TLRs) TLR3, TLR7, TLR8, and TLR9, which are essential for antiviral immunity. Overactive TLR7 signaling induced by recognition of self-nucleic acids has been implicated in systemic lupus erythematosus (SLE). Here, we report UNC93B1 variants (E92G and R336L) in four patients with early-onset SLE. Patient cells or mouse macrophages carrying the UNC93B1 variants produced high amounts of TNF-α and IL-6 and upon stimulation with TLR7/TLR8 agonist, but not with TLR3 or TLR9 agonists. E92G causes UNC93B1 protein instability and reduced interaction with TLR7, leading to selective TLR7 hyperactivation with constitutive type I IFN signaling. Thus, UNC93B1 regulates TLR subtype-specific mechanisms of ligand recognition. Our findings establish a pivotal role for UNC93B1 in TLR7-dependent autoimmunity and highlight the therapeutic potential of targeting TLR7 in SLE.

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Transcriptomic Predictors of Paradoxical Cryptococcosis-Associated Immune Reconstitution Inflammatory Syndrome

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