Innate immune system activation in zebrafish and cellular models of Diamond Blackfan Anemia

Sci Rep. 2018 Mar 26;8(1):5165. doi: 10.1038/s41598-018-23561-6.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Activin Receptors / antagonists & inhibitors
  • Activins / metabolism
  • Anemia, Diamond-Blackfan / immunology*
  • Anemia, Diamond-Blackfan / metabolism*
  • Animals
  • Arginine / analogs & derivatives
  • Arginine / pharmacology
  • Benzamides / pharmacology
  • Benzhydryl Compounds / pharmacology
  • Complement C3a / antagonists & inhibitors
  • Complement C3a / metabolism
  • Dioxoles / pharmacology
  • Disease Models, Animal
  • Humans
  • Immunity, Innate / physiology*
  • Interferons / metabolism
  • K562 Cells
  • RNA, Small Interfering / metabolism
  • Receptor, Transforming Growth Factor-beta Type I / antagonists & inhibitors
  • Ribosomal Proteins / metabolism
  • Toll-Like Receptor 3 / antagonists & inhibitors
  • Toll-Like Receptor 3 / metabolism
  • Transforming Growth Factor beta / metabolism
  • Tumor Suppressor Protein p53 / metabolism
  • Up-Regulation
  • Zebrafish / embryology
  • Zebrafish / immunology*
  • Zebrafish / metabolism*
  • Zebrafish Proteins / metabolism


  • 4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide
  • Benzamides
  • Benzhydryl Compounds
  • Dioxoles
  • RNA, Small Interfering
  • RPS19 protein, zebrafish
  • Ribosomal Proteins
  • SB 290157
  • TLR3 protein, human
  • Toll-Like Receptor 3
  • Transforming Growth Factor beta
  • Tumor Suppressor Protein p53
  • Zebrafish Proteins
  • ribosomal protein S19
  • Activins
  • Complement C3a
  • Interferons
  • Arginine
  • Activin Receptors
  • Receptor, Transforming Growth Factor-beta Type I