Abstract
Deficiency of ribosomal proteins (RPs) leads to Diamond Blackfan Anemia (DBA) associated with anemia, congenital defects, and cancer. While p53 activation is responsible for many features of DBA, the role of immune system is less defined. The Innate immune system can be activated by endogenous nucleic acids from non-processed pre-rRNAs, DNA damage, and apoptosis that occurs in DBA. Recognition by toll like receptors (TLRs) and Mda5-like sensors induces interferons (IFNs) and inflammation. Dying cells can also activate complement system. Therefore we analyzed the status of these pathways in RP-deficient zebrafish and found upregulation of interferon, inflammatory cytokines and mediators, and complement. We also found upregulation of receptors signaling to IFNs including Mda5, Tlr3, and Tlr9. TGFb family member activin was also upregulated in RP-deficient zebrafish and in RPS19-deficient human cells, which include a lymphoid cell line from a DBA patient, and fetal liver cells and K562 cells transduced with RPS19 shRNA. Treatment of RP-deficient zebrafish with a TLR3 inhibitor decreased IFNs activation, acute phase response, and apoptosis and improved their hematopoiesis and morphology. Inhibitors of complement and activin also had beneficial effects. Our studies suggest that innate immune system contributes to the phenotype of RPS19-deficient zebrafish and human cells.
Highlights
Diamond-Blackfan Anemia (DBA) is a bone marrow failure syndrome, which is characterized by congenital malformations and cancer[1,2]
Altered expression of genes associated with inflammation, NFkB and TNF signaling have been found in fibroblasts from Diamond Blackfan Anemia (DBA) patients such as ~14 fold increase in TNF alpha induced protein 3 (TNFAIP3)[19]
We created an Rps19-deficient fish using a morpholino, which was highly specific as was confirmed by using an alternative translational morpholino, rescue of morphant phenotype by rps[19] mRNA, and use of scrambled morpholino that had no effect on embryos at any dose studied up to 13 ng per embryo[9]
Summary
Diamond-Blackfan Anemia (DBA) is a bone marrow failure syndrome, which is characterized by congenital malformations and cancer[1,2]. Activation of p53 independent signaling pathways in DBA has been reported[12,14] their role and interaction with the p53 network is not well defined. Some data suggest upregulation of interferon (IFN) signaling and inflammation in DBA. The analysis of erythrocyte cytoplasmic proteome from DBA patients cells show increased presence of IFN targets and immunoproteasome components[17]. Increased expression of genes associated with IFN and TNF pathways has been noted in hematopoietic progenitors[18]. Interferon regulatory factor 9 (IRF9) essential for type I IFN signaling was 2.84 fold upregulated in multipotential hematopoietic progenitors. Altered expression of genes associated with inflammation, NFkB and TNF signaling have been found in fibroblasts from DBA patients such as ~14 fold increase in TNF alpha induced protein 3 (TNFAIP3)[19]. The role of complement in DBA has not been studied
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